Revised clean version Ceulemans PDS-18-0472

Health products’ and substance use among pregnant women visiting a tertiary hospital in Belgium: a cross-sectional study Health products’ & substance use during pregnancy Michael Ceulema

Health products’ and substance use among pregnant women visiting a tertiary hospital in Belgium: a cross-sectional study

Health products’ & substance use during pregnancy

Michael Ceulemans, Kristel Van Calsteren, Karel Allegaert, Veerle Foulon

Michael Ceulemans (corresponding author)

Department of Pharmaceutical and Pharmacological Sciences

Clinical Pharmacology and Pharmacotherapy, KU Leuven

Herestraat 49, Box 521, 3000 Leuven, Belgium

e-mail: Michael.Ceulemans@kuleuven.be

ORCID: 0000-0002-4130-5869

Kristel Van Calsteren

Department of Obstetrics & Gynecology, University Hospital Gasthuisberg Leuven, Belgium

Department of Development and Regeneration, Woman and Child, KU Leuven, Leuven, Belgium

ORCID: 0000-0002-2438-6783

Karel Allegaert

Department of Development and Regeneration, Woman and Child, KU Leuven, Leuven, Belgium

Department of Pediatrics, Division of Neonatology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands

ORCID: 0000-0001-9921-5105

Veerle Foulon

Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, KU Leuven, Leuven, Belgium

ORCID: 0000-0002-4053-3915

Key words:

pharmacoepidemiology, pregnancy, drug utilization, preconception care, folic acid, Belgium

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Key points

• First study to investigate the prevalence and type of health products used among pregnant women visiting a tertiary hospital in Belgium

• Prevalence of medication use during the preceding week was 52%; pregnancy vitamins were used by 86%

• Paracetamol, levothyroxine and antacids were the most commonly used medicines during the preceding week

• Preconception lifestyle changes were poorly implemented Only 56% initiated folic acid supplementation at least one month before pregnancy Prevalence of alcohol use and/or smoking was 6%; women mainly stopped after pregnancy diagnosis

• Public campaigns and interventions are needed to improve preconception care and counselling

Word count (excluding abstract, tables, figures and references): 3 115 words

Prior postings and presentations:

Preliminary results described in this paper have been presented during the following international conferences:

• 16th Meeting of the European Society for Developmental Perinatal and Paediatric Pharmacology, 20-23 June

2017, Leuven, Belgium (short oral presentation)

• 28th Conference of the European Network of Teratology Information Services, 2-5 September 2017, Budapest, Hungary (poster presentation)

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Purpose:

To investigate the prevalence and type of health products used among pregnant women visiting a tertiary hospital in Belgium, as well as who advises these products, where women buy these products, which determinants are associated with medication and pregnancy vitamin intake, and preconception lifestyle changes such as folic acid intake and substance use

Methods:

A cross-sectional study was performed at the outpatient obstetrics clinics of the University Hospital Leuven, Belgium between November 2016 and March 2017 All pregnant women ≥18 years and understanding Dutch, French or English were asked to participate in an online survey

Results:

In total, 379 pregnant women participated Prevalence of medication use during the preceding week was 52% Paracetamol (14%), levothyroxine (13%) and antacids (9%) were the most frequently used medicines Pregnancy vitamins were used by 86% of women, while 97% had used a pregnancy vitamin somewhere during pregnancy Only 56% initiated folic acid supplementation at least one month before pregnancy Preconception use of folic acid among women following assisted reproductive technology was 73% Inappropriate use of health products was observed

among 3% of women Prevalence of alcohol use and/or smoking during the preceding week was 6% Alcohol and

smoking cessation mainly occurred after pregnancy diagnosis

Conclusion:

Pregnant women living in Belgium frequently use medicines, pregnancy vitamins, and other health products Preconception lifestyle changes such as folic acid intake and alcohol and smoking cessation are poorly implemented Public campaigns and interventions are needed to improve preconception care and counselling

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1 INTRODUCTION

Pregnancy-related ailments and preexisting comorbidities may necessitate the use of prescription and over-the-counter (OTC) medicines during pregnancy.(1, 2) Due to dissimilarities in study design, reporting and OTC statute between countries, prevalence of prescription medication use varies between 27 and 93%.(3) Use of OTC medicines during pregnancy has been observed in more than 65% of pregnancies.(4-6) Medication use during pregnancy is not only common, it has also increased over the past decades, at least in developed countries.(7) At the same time, pregnant women may overestimate teratogenic risks of medicines, thereby potentially compromising necessary medical treatment.(5, 8) Over the last years, questions have also raised about the ease to purchase potentially harmful products via Internet without medical counselling.(9, 10) In addition, medication lending has been observed among women of reproductive age, even for teratogenic medicines like isotretinoin.(11, 12) Hence, medication counselling during pregnancy poses challenges to healthcare professionals (HCPs)

Besides prescription and OTC medicines, pregnant women can also be exposed to other health products.(13) Although efficacy and safety data for herbal supplements are limited, pregnant women commonly use these kind of products (14) Relatives and friends were shown to act as an important source of information about herbal remedies, while caregivers may not be informed about the use of these products.(15) Besides other health products, maternal use of substances and preconception intake of folic acid in the prevention of neural tube defects also deserves attention Alcohol, tobacco and illicit drugs are preferably avoided since maternal use is associated with increased risk of pregnancy complications and poor infant outcomes.(16) Recent findings have demonstrated the underestimation of the prevalence of fetal alcohol spectrum disorders(17, 18), as well as the negative effects of even low alcohol intake during pregnancy on the craniofacial development of newborns.(19) With regard to preconception intake of folic acid, previous studies have shown that prevalence estimates might differ between different pregnant populations.(20, 21)

In general, epidemiological data on medication and health products’ use and preconception lifestyle changes can reveal current pitfalls and opportunities to improve maternal and fetal health.(22) Unfortunately, Belgian data are limited Therefore, the aim of this study was to investigate the prevalence and type of health products used among pregnant women visiting a tertiary hospital in Belgium, as well as who advises these products, where women buy these products, which determinants are associated with medication and pregnancy vitamin intake, and preconception lifestyle changes such as folic acid intake and substance use

2 METHODS

2.1 Study design and population

A cross-sectional study was performed at the outpatient obstetrics clinics of the University Hospital Leuven, Belgium between November 2016 and March 2017 All pregnant women ≥18 years, understanding Dutch, French or English and visiting the obstetrics clinics in the context of their antenatal care were approached in person by a member of the research team while waiting for their consultation and were asked to complete an online survey A Dutch, French and

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English version was available through an university website for which a personal login was required, and was launched after a draft version was pilot tested in ten pregnant women The online approach enabled respondents to initiate or finish the survey at home Written informed consent was obtained from participants

2.2 Survey

The survey was part of the PREVIM-study (PREgnancy related use of Vitamins and Medication) and consisted of questions about socio-demographic and pregnancy-related characteristics, as well as health products’ and substance use during the preceding week (see Supplementary Material) Health products were divided into four categories: medicines, pregnancy vitamins, supplements and other health products Respondents could check the correctness of their answers by using a database, incorporated in the survey, containing more than 100 000 pictures of health products available in Belgium

2.3 Data analysis

Descriptive statistics were used to report patient characteristics and prevalence of health products’ and substance use Data cleaning focused on correct categorization of the health products used In this study, preparations were classified according to the official registration dossier For ingredients as vitamin D and iron, manufacturers can choose between registration as ‘medicine’ or as ‘supplement’ Products were defined ‘medicines’ if they were listed

in the official Belgian medication registry Further classification of medicines was performed according to the WHO Anatomical Therapeutic Chemical (ATC) classification system,(23) while supplements were categorized based on ingredients Any formal degree obtained after secondary school was considered ‘higher education’

Multivariate logistic regression was used to identify socio-demographic and pregnancy-related characteristics associated with an increased likelihood of medicines and pregnancy vitamin use Chi-square tests were used to test for differences in preconception lifestyle changes between women with and without assisted reproductive technology (ART) prior to current pregnancy A 5% significance level was assumed for all tests Data analysis was performed with SPSS version 24

3 RESULTS

3.1 Characteristics of study population

In total, 379 women participated in the study This corresponds to a response rate of 87% Median age of women was

31 years (range: 18-47) Respondents were almost equally divided over the gestational trimesters (largest group in trimester 1), and 50% was nulliparous A detailed overview of study participants’ characteristics is shown in Table 1 and 2

3.2 Prevalence of health products’ use during pregnancy

Of all women, 98% used at least one health product during the preceding week Of them, 56% used 1 or 2 products, 37% used 3 to 5 products and 6% more than 5 products Prevalence of medication use during the preceding week

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was 52% Among medicines users, 53% used one medicine, 32% two medicines and 15% at least three medicines Among all women, 36% used a prescription medicine and 28% an OTC-medicine during the preceding week Most prevalent ATC categories were alimentary tract and metabolism (17%), nervous system (16%), blood and blood forming organs (14%) and systemic hormonal preparations (14%) The most frequently used medicines are shown in Table 3 Intake of selective-serotonin reuptake inhibitors (SSRIs) was observed among less than 2% of the women With regard to drug-drug interactions, 72% of levothyroxine users showed a potential interaction risk because of concomitant use of antacids, iron or magnesium supplements In general, medicines were initiated during pregnancy

in 68% of the cases The use of 35% of medicines initiated prior to pregnancy was changed during pregnancy Finally, OTC medicines accounted for 90% of medicines initiated on personal initiative (especially paracetamol and antacids)

Prevalence of pregnancy vitamin use during the preceding week was 86%, of which 26% only used folic acid and 74% multivitamins Around 60% used a pregnancy vitamin containing iron and vitamin D 97% of women had used

a pregnancy vitamin somewhere during pregnancy Prevalence of folic acid intake in first, second and third trimester was 97%, 82% and 75%, respectively Of all women, 56% started using minimum 0.4 mg folic acid at least one month prior to pregnancy; 73% of women took folic acid in the first 4 weeks of pregnancy 73% of women whose pregnancy followed after ART started using folic acid at least one month prior to pregnancy, which was significantly higher compared to the 53% of women who became pregnant spontaneously (p=0.008)

Supplements, other than pregnancy vitamins, were used by 15% of women, with magnesium (44%), vitamin D (23%) and omega fatty acids (23%) as most commonly used ingredients The overall prevalence of vitamin D and iron supplementation was 5% and 10% when medicines and supplements were taken into account, and 63% and 64%

if pregnancy vitamins were included Other health products were used by about 50% of women, mainly stretch mark creams (80% of users) Inappropriate products such as essential oils or preparations containing alcohol were used by 3% of women Supplements and other health products were initiated during pregnancy in 65% and 78% of the cases When products were initiated before pregnancy, changes during pregnancy happened in only 15% of the cases

3.3 Motivations and behavior towards health products’ use during pregnancy

Motivations and behavior towards pregnancy vitamin intake and reluctance to health products during pregnancy was also studied About 25% of women who used a pregnancy vitamin in the last week had already used another one during this pregnancy 60% of these women changed to another preparation because the obstetrician / general practitioner (48%) or pharmacist (14%) argued that it was superior More than 20% of women switched to another vitamin because of personal beliefs about insufficient vitamin composition Gastro-intestinal tolerance or financial aspects were no important incentives for change Finally, one-third of women answered that they had already avoided the use of health products during the current pregnancy

3.4 Factors associated with medication and pregnancy vitamin use

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Maternal age and gestational trimester were associated with medication and pregnancy vitamin use during pregnancy Increasing age was associated with an increased likelihood of using pregnancy vitamins (OR 1.16; CI: 1.08-1.25) and prescription medicines (OR 1.06; CI: 1.01-1.11) The influence of gestational trimester differed for medication and pregnancy vitamins Compared to first trimester pregnancies, women in the second (OR 0.15; CI: 0.06-0.43) and third trimester (OR 0.13; CI: 0.05-0.34) were less likely to take pregnancy vitamins However, third trimester women were more likely to take medicines compared to the first trimester (OR 1.96; CI 1.21-3.18) Secondly, parity, maternal age, education level and education in healthcare were associated with pregnancy vitamin use initiated on personal initiative A decreased likelihood of self-initiation of pregnancy vitamins was found among nulliparae (OR 0.28; CI 0.16-0.51), low educated women (OR 0.31; CI: 0.14-0.66) and women not educated in healthcare (OR 0.42; CI: 0.24-0.76), while the likelihood increased with increasing age (OR 1.08; CI: 1.01-1.16) Finally, preconception folic acid intake was associated with parity, age, marital status, country of birth and occupation in healthcare The likelihood of preconception folic acid intake increased with increasing age (OR 1.11;

CI 1.05-1.17) and among nulliparae (OR 2.20; CI 1.37-3.53), women with a partner (OR 8.20; CI 2.16-31.15), born

in Belgium (OR 2.16; CI 1.27-3.69) and occupied in healthcare (OR 2.42; CI 1.32-4.45)

3.5 Counselling and supply of health products during pregnancy

Medicines and pregnancy vitamins were most often advised by obstetricians and general practitioners For supplements and other health products, however, advice of doctors only accounted for 23% of products Medicines and pregnancy vitamins were most frequently bought in public pharmacies (97% and 91%, respectively), mostly in the woman’s regular pharmacy Although public pharmacies were still considered the most important source of other health products (59%), importance of supermarket, groceries, healthy food and herb shops and product samples was higher Product initiation after personal decision or upon recommendation of relatives and friends was also more important for other health products (see Table 4 and 5)

3.6 Pregnancy tests: purchase and advice

84% of women had used a urinary pregnancy test to confirm pregnancy Half of these women bought the test in a public pharmacy, while grocery stores, supermarkets and online purchase accounted as other supply channels Remarkably, pharmacists did not provide any information in 43% of the cases Furthermore, the importance of folic acid intake was mentioned in only 14% of the situations More information about the pharmacist’s advice as perceived by the women is shown in Supplementary Material – 2

3.7 Preconception lifestyle changes

To investigate additional lifestyle changes besides preconception intake of folic acid, women were asked about their substance use before and during pregnancy Prior to pregnancy, alcohol use (64%) was more prevalent than smoking (12%) and use of illicit drugs (3%) 6% of pregnant women reported to use alcohol and/or cigarettes during the preceding week (see Table 6); 1% used both Women who used alcohol or smoked before pregnancy, mainly stopped after pregnancy diagnosis (78% and 83%, respectively)

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In general, 32% of women confirmed to have made preconception lifestyle changes, regardless of folic acid intake and substance use Half of them answered eating more fruits and vegetables, drinking more water, drinking less caffeine containing beverages (coffee, cola) or paying extra attention to what (not) to eat One-fourth of women reported doing more physical activity, while vaccine status was checked by 20% of the women

4 DISCUSSION

In this study, we aimed to investigate health products’ and substance use among pregnant women visiting a tertiary hospital in Belgium First, we found that half of the pregnant women used at least one registered medicine during the preceding week, with 36% using a prescription medicine and 28% an OTC medicine Paracetamol, levothyroxine and antacids were the most frequently used medicines, thereby confirming previous findings for paracetamol and antacids.(4-6) The estimated prevalence of levothyroxine use, however, was four-fold higher than observed in other pregnancy cohorts(6, 7, 24, 25), likely due to the study setting and the clinical protocol with a low threshold of initiating treatment which was followed in the study period (TSH >2.5 mIU/L between 7 and 11 weeks, TSH >3 from 12w onwards) Second, the prevalence of pregnancy vitamin use during the preceding week was 86% and increased to 97% if the entire pregnancy was taken into account The high prevalence of multivitamin intake and vitamin D supplementation (≥60%) was in line with previous findings.(26, 27) Third, the high prevalence of thyroid hormone, iron, magnesium supplements and multivitamins increased the likelihood of drug-drug interactions due to concomitant intake These data should motivate HCPs to be vigilant for the use of drug combinations in this population, in order

to prevent suboptimal maternal treatment With regard to safety aspects, the use of other health products also deserves our attention Health products such as essential oils or alcohol containing preparations have a negative benefit-risk ratio during pregnancy Although their use was rather limited, they were often started on personal initiative or suggested by family and friends and were commonly purchased via supermarkets, shops or received as product samples(13, 14) Therefore, HCPs should be aware that pregnant women might use and purchase inappropriate products without professional advice In the future, HCPs need to discuss the use of all kind of health products when counselling pregnant women

Furthermore, we found that preconception intake of folic acid is still insufficient in Belgium, (26, 27) which calls HCPs and policy makers upon action Although a high prevalence of folic acid intake during the preceding week was observed, half of the women started too late and more than 25% of pregnant women did not use folic acid in the first

4 weeks Since no increase in folic acid intake was observed over the last years, (26, 27) we can assume that recent initiatives, such as the establishment of an evidence-based website on preconception care in Belgium in 2015,(28) did not have sufficient positive impact on the preconception folic acid intake It is obvious that all HCPs involved in prenatal care should discuss the intake of folic acid, preferably during each contact with (pregnant) women To assure folic acid initiation before neural tube closure, community pharmacists have the opportunity to discuss folic acid when dispensing pregnancy tests, especially when women have not yet started it.(29) In our cohort, folic acid was mentioned in only 14% of the pharmacy encounters related to pregnancy tests, which was in line with a previous pilot study.(30) As a result, less than 10% of women who used a urinary pregnancy test were informed about the importance of preconception folic acid when purchasing a test, assuming that other supply channels do not provide

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any information about folic acid Surprisingly, preconception use of folic acid in ART users was also insufficient, despite frequent visits to the fertility center and supposed intensive follow-up This finding definitely needs further investigation and urges for strategies to tackle current challenges

Other preconception opportunities that have been identified relate to alcohol use and smoking Although it has previously been shown that women perceive alcohol and cigarettes as most risky products during pregnancy(5), prevalence for alcohol use and smoking in our cohort was 6% Even though higher prevalences were found in other countries,(31-35) this finding is worrying Furthermore, most women stopped drinking alcohol and/or smoking only after pregnancy diagnosis, as shown earlier.(36, 37) Poor changes in substance use prior to pregnancy might expose the fetus to teratogens during the most vulnerable weeks of pregnancy In addition, preconception changes in dietary habits barely occurred.(36, 38) Hence, preconception care should be further developed and implemented in Belgium Luckily, a recent study showed that reproductive-aged women in Belgium have interest in receiving more preconception care in the future.(39)

Data were collected using a self-reporting survey Survey completion occured outside the direct supervision of an involved HCP, which might have prevented women from giving socially desirable answers Reliability of product information was pursued by incorporating an up-to-date, picture-based database of health products available in Belgium To ensure completeness of data collection, the main question about health products’ use was asked four times In addition, respondents were informed that individual answers would be encoded, thereby stimulating participants to disclose all applicable health products Finally, women were asked to report only the use of medicines and other health products during the last seven days, thereby limiting recall bias and maximizing correctness of prevalence estimates and type of products

Some limitations should also be kept in mind when interpreting the findings The study was limited to women visiting a tertiary hospital Compared to general and pregnancy-related population data, study participants slighty differed with respect to age, highest degree of education and ART use before the current pregnancy.(40-42) As medication use increases with age, overestimation of the prevalence of medication use during the preceding week is possible In contrast, highly educated women seem to have a higher threshold to use medicines during pregnancy(43), which in turn could have led to an underestimation of the prevalence Nonetheless, an underestimation of the total medication exposure during pregnancy is expected, as only medication use during the last week was studied With regard to preconception folic acid intake, the prevalence in the general population might be even lower, as the study findings indicated that folic acid intake increases with age and among women occupied in healthcare In this study, pregnant women who did not understand Dutch, French or English were excluded In the future, it would be interesting to study health products’ and substance use among these group of women From a fetal-maternal safety perspective, however, the study findings as described in the current paper are considered to be important for HCPs and policy makers involved in prenatal care within and outside Belgium

5 CONCLUSION

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Pregnant women visiting a tertiary hospital in Belgium frequently use medicines, pregnancy vitamins, and other health products Preconception lifestyle changes such as folic acid intake and alcohol and smoking cessation are poorly implemented These findings emphasize the importance of counselling on preconception lifestyle changes and

on the safe use of health products during pregnancy Public campaigns and interventions are needed to improve preconception care and to improve HCPs’ counselling

ETHICS STATEMENT

Ethical approval was granted from the local Medical Ethics committee and the study was conducted in accordance with the declaration of Helsinki and applicable privacy requirements

AKNOWLEDGEMENTS

We want to thank the Faculty of Pharmaceutical Sciences and the Academic Foundation Leuven for supporting the research project We are also grateful to the midwives working at the consultation of the University Hospital of Leuven, masterstudents, Martial Luyts (statistician), and Medipim (database) for their contribution to data collection and analyses

CONFLICT OF INTEREST

The authors declare no conflict of interest

AUTHORS’ CONTRIBUTION

MC carried out data collection, data analysis and drafted the initial and final version of the manuscript All authors contributed to the study design and reviewed and approved the initial and final version of the manuscript

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