Revised clean version Ceulemans PDS-18-0472

1Health products’ and substance use among pregnant women visiting a tertiary hospital in Belgium: a cross- 2sectional study 3Health products’ & substance use during pregnancy 5Michael Ceulemans, Kristel Van Calsteren, Karel Allegaert, Veerle Foulon 7Michael Ceulemans (corresponding author) 8Department of Pharmaceutical and Pharmacological Sciences 9Clinical Pharmacology and Pharmacotherapy, KU Leuven 10Herestraat 49, Box 521, 3000 Leuven, Belgium 11e-mail: Michael.Ceulemans@kuleuven.be 12ORCID: 0000-0002-4130-5869 13 14Kristel Van Calsteren 15Department of Obstetrics & Gynecology, University Hospital Gasthuisberg Leuven, Belgium 16Department of Development and Regeneration, Woman and Child, KU Leuven, Leuven, Belgium 17ORCID: 0000-0002-2438-6783 18 19Karel Allegaert 20Department of Development and Regeneration, Woman and Child, KU Leuven, Leuven, Belgium 21Department of Pediatrics, Division of Neonatology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The 22Netherlands 23ORCID: 0000-0001-9921-5105 24 25Veerle Foulon 26Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, KU 27Leuven, Leuven, Belgium 28ORCID: 0000-0002-4053-3915 29 30 31Key words: 32pharmacoepidemiology, pregnancy, drug utilization, preconception care, folic acid, Belgium 33 34 35 36 37 38Key points 39 • First study to investigate the prevalence and type of health products used among pregnant women visiting a 40 41 • Prevalence of medication use during the preceding week was 52%; pregnancy vitamins were used by 86% 42 • Paracetamol, levothyroxine and antacids were the most commonly used medicines during the preceding 43 44 45 46 47 tertiary hospital in Belgium 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 48 49Word count (excluding abstract, tables, figures and references): 115 words 50 51Prior postings and presentations: 52Preliminary results described in this paper have been presented during the following international conferences: 53 54 55 56 • 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) 57 58 59 60 61 62 63 64 65 66 67 68 69 2 70 71ABSTRACT 72Purpose: 73To investigate the prevalence and type of health products used among pregnant women visiting a tertiary hospital in 74Belgium, as well as who advises these products, where women buy these products, which determinants are 75associated with medication and pregnancy vitamin intake, and preconception lifestyle changes such as folic acid 76intake and substance use 77 78Methods: 79A cross-sectional study was performed at the outpatient obstetrics clinics of the University Hospital Leuven, Belgium 80between November 2016 and March 2017 All pregnant women ≥18 years and understanding Dutch, French or 81English were asked to participate in an online survey 82 83Results: 84In total, 379 pregnant women participated Prevalence of medication use during the preceding week was 52% 85Paracetamol (14%), levothyroxine (13%) and antacids (9%) were the most frequently used medicines Pregnancy 86vitamins were used by 86% of women, while 97% had used a pregnancy vitamin somewhere during pregnancy Only 8756% initiated folic acid supplementation at least one month before pregnancy Preconception use of folic acid among 88women following assisted reproductive technology was 73% Inappropriate use of health products was observed 89among 3% of women Prevalence of alcohol use and/or smoking during the preceding week was 6% Alcohol and 90smoking cessation mainly occurred after pregnancy diagnosis 91 92Conclusion: 93Pregnant women living in Belgium frequently use medicines, pregnancy vitamins, and other health products 94Preconception lifestyle changes such as folic acid intake and alcohol and smoking cessation are poorly implemented 95Public campaigns and interventions are needed to improve preconception care and counselling 96 97 98 99 100 101 102 103 104 3 105 106 INTRODUCTION 107Pregnancy-related ailments and preexisting comorbidities may necessitate the use of prescription and over-the- 108counter (OTC) medicines during pregnancy (1, 2) Due to dissimilarities in study design, reporting and OTC statute 109between countries, prevalence of prescription medication use varies between 27 and 93% (3) Use of OTC medicines 110during pregnancy has been observed in more than 65% of pregnancies (4-6) Medication use during pregnancy is not 111only common, it has also increased over the past decades, at least in developed countries (7) At the same time, 112pregnant women may overestimate teratogenic risks of medicines, thereby potentially compromising necessary 113medical treatment.(5, 8) Over the last years, questions have also raised about the ease to purchase potentially harmful 114products via Internet without medical counselling (9, 10) In addition, medication lending has been observed among 115women of reproductive age, even for teratogenic medicines like isotretinoin (11, 12) Hence, medication counselling 116during pregnancy poses challenges to healthcare professionals (HCPs) 117 118Besides prescription and OTC medicines, pregnant women can also be exposed to other health products (13) Although 119efficacy and safety data for herbal supplements are limited, pregnant women commonly use these kind of products 120(14) Relatives and friends were shown to act as an important source of information about herbal remedies, while 121caregivers may not be informed about the use of these products (15) Besides other health products, maternal use of 122substances and preconception intake of folic acid in the prevention of neural tube defects also deserves attention 123Alcohol, tobacco and illicit drugs are preferably avoided since maternal use is associated with increased risk of 124pregnancy complications and poor infant outcomes (16) Recent findings have demonstrated the underestimation of the 125prevalence of fetal alcohol spectrum disorders (17, 18), as well as the negative effects of even low alcohol intake during 126pregnancy on the craniofacial development of newborns.(19) With regard to preconception intake of folic acid, 127previous studies have shown that prevalence estimates might differ between different pregnant populations (20, 21) 128 129In general, epidemiological data on medication and health products’ use and preconception lifestyle changes can 130reveal current pitfalls and opportunities to improve maternal and fetal health (22) Unfortunately, Belgian data are 131limited Therefore, the aim of this study was to investigate the prevalence and type of health products used among 132pregnant women visiting a tertiary hospital in Belgium, as well as who advises these products, where women buy 133these products, which determinants are associated with medication and pregnancy vitamin intake, and preconception 134lifestyle changes such as folic acid intake and substance use 135 136 METHODS 1372.1 Study design and population 138A cross-sectional study was performed at the outpatient obstetrics clinics of the University Hospital Leuven, Belgium 139between November 2016 and March 2017 All pregnant women ≥18 years, understanding Dutch, French or English 140and visiting the obstetrics clinics in the context of their antenatal care were approached in person by a member of the 141research team while waiting for their consultation and were asked to complete an online survey A Dutch, French and 4 142English version was available through an university website for which a personal login was required, and was 143launched after a draft version was pilot tested in ten pregnant women The online approach enabled respondents to 144initiate or finish the survey at home Written informed consent was obtained from participants 145 1462.2 Survey 147The survey was part of the PREVIM-study (PREgnancy related use of Vitamins and Medication) and consisted of 148questions about socio-demographic and pregnancy-related characteristics, as well as health products’ and substance 149use during the preceding week (see Supplementary Material) Health products were divided into four categories: 150medicines, pregnancy vitamins, supplements and other health products Respondents could check the correctness of 151their answers by using a database, incorporated in the survey, containing more than 100 000 pictures of health 152products available in Belgium 153 1542.3 Data analysis 155Descriptive statistics were used to report patient characteristics and prevalence of health products’ and substance use 156Data cleaning focused on correct categorization of the health products used In this study, preparations were 157classified according to the official registration dossier For ingredients as vitamin D and iron, manufacturers can 158choose between registration as ‘medicine’ or as ‘supplement’ Products were defined ‘medicines’ if they were listed 159in the official Belgian medication registry Further classification of medicines was performed according to the WHO 160Anatomical Therapeutic Chemical (ATC) classification system,(23) while supplements were categorized based on 161ingredients Any formal degree obtained after secondary school was considered ‘higher education’ 162Multivariate logistic regression was used to identify socio-demographic and pregnancy-related characteristics 163associated with an increased likelihood of medicines and pregnancy vitamin use Chi-square tests were used to test 164for differences in preconception lifestyle changes between women with and without assisted reproductive technology 165(ART) prior to current pregnancy A 5% significance level was assumed for all tests Data analysis was performed 166with SPSS version 24 167 168 169 RESULTS 1703.1 Characteristics of study population 171In total, 379 women participated in the study This corresponds to a response rate of 87% Median age of women was 17231 years (range: 18-47) Respondents were almost equally divided over the gestational trimesters (largest group in 173trimester 1), and 50% was nulliparous A detailed overview of study participants’ characteristics is shown in Table 174and 175 1763.2 Prevalence of health products’ use during pregnancy 177Of all women, 98% used at least one health product during the preceding week Of them, 56% used or products, 17837% used to products and 6% more than products Prevalence of medication use during the preceding week 5 179was 52% Among medicines users, 53% used one medicine, 32% two medicines and 15% at least three medicines 180Among all women, 36% used a prescription medicine and 28% an OTC-medicine during the preceding week Most 181prevalent ATC categories were alimentary tract and metabolism (17%), nervous system (16%), blood and blood 182forming organs (14%) and systemic hormonal preparations (14%) The most frequently used medicines are shown in 183Table Intake of selective-serotonin reuptake inhibitors (SSRIs) was observed among less than 2% of the women 184With regard to drug-drug interactions, 72% of levothyroxine users showed a potential interaction risk because of 185concomitant use of antacids, iron or magnesium supplements In general, medicines were initiated during pregnancy 186in 68% of the cases The use of 35% of medicines initiated prior to pregnancy was changed during pregnancy 187Finally, OTC medicines accounted for 90% of medicines initiated on personal initiative (especially paracetamol and 188antacids) 189 190Prevalence of pregnancy vitamin use during the preceding week was 86%, of which 26% only used folic acid and 19174% multivitamins Around 60% used a pregnancy vitamin containing iron and vitamin D 97% of women had used 192a pregnancy vitamin somewhere during pregnancy Prevalence of folic acid intake in first, second and third trimester 193was 97%, 82% and 75%, respectively Of all women, 56% started using minimum 0.4 mg folic acid at least one 194month prior to pregnancy; 73% of women took folic acid in the first weeks of pregnancy 73% of women whose 195pregnancy followed after ART started using folic acid at least one month prior to pregnancy, which was significantly 196higher compared to the 53% of women who became pregnant spontaneously (p=0.008) 197 198Supplements, other than pregnancy vitamins, were used by 15% of women, with magnesium (44%), vitamin D 199(23%) and omega fatty acids (23%) as most commonly used ingredients The overall prevalence of vitamin D and 200iron supplementation was 5% and 10% when medicines and supplements were taken into account, and 63% and 64% 201if pregnancy vitamins were included Other health products were used by about 50% of women, mainly stretch mark 202creams (80% of users) Inappropriate products such as essential oils or preparations containing alcohol were used by 2033% of women Supplements and other health products were initiated during pregnancy in 65% and 78% of the cases 204When products were initiated before pregnancy, changes during pregnancy happened in only 15% of the cases 205 2063.3 Motivations and behavior towards health products’ use during pregnancy 207Motivations and behavior towards pregnancy vitamin intake and reluctance to health products during pregnancy was 208also studied About 25% of women who used a pregnancy vitamin in the last week had already used another one 209during this pregnancy 60% of these women changed to another preparation because the obstetrician / general 210practitioner (48%) or pharmacist (14%) argued that it was superior More than 20% of women switched to another 211vitamin because of personal beliefs about insufficient vitamin composition Gastro-intestinal tolerance or financial 212aspects were no important incentives for change Finally, one-third of women answered that they had already 213avoided the use of health products during the current pregnancy 214 2153.4 Factors associated with medication and pregnancy vitamin use 6 216Maternal age and gestational trimester were associated with medication and pregnancy vitamin use during 217pregnancy Increasing age was associated with an increased likelihood of using pregnancy vitamins (OR 1.16; CI: 2181.08-1.25) and prescription medicines (OR 1.06; CI: 1.01-1.11) The influence of gestational trimester differed for 219medication and pregnancy vitamins Compared to first trimester pregnancies, women in the second (OR 0.15; CI: 2200.06-0.43) and third trimester (OR 0.13; CI: 0.05-0.34) were less likely to take pregnancy vitamins However, third 221trimester women were more likely to take medicines compared to the first trimester (OR 1.96; CI 1.21-3.18) 222Secondly, parity, maternal age, education level and education in healthcare were associated with pregnancy vitamin 223use initiated on personal initiative A decreased likelihood of self-initiation of pregnancy vitamins was found among 224nulliparae (OR 0.28; CI 0.16-0.51), low educated women (OR 0.31; CI: 0.14-0.66) and women not educated in 225healthcare (OR 0.42; CI: 0.24-0.76), while the likelihood increased with increasing age (OR 1.08; CI: 1.01-1.16) 226Finally, preconception folic acid intake was associated with parity, age, marital status, country of birth and 227occupation in healthcare The likelihood of preconception folic acid intake increased with increasing age (OR 1.11; 228CI 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 229in Belgium (OR 2.16; CI 1.27-3.69) and occupied in healthcare (OR 2.42; CI 1.32-4.45) 230 2313.5 Counselling and supply of health products during pregnancy 232Medicines and pregnancy vitamins were most often advised by obstetricians and general practitioners For 233supplements and other health products, however, advice of doctors only accounted for 23% of products Medicines 234and pregnancy vitamins were most frequently bought in public pharmacies (97% and 91%, respectively), mostly in 235the woman’s regular pharmacy Although public pharmacies were still considered the most important source of other 236health products (59%), importance of supermarket, groceries, healthy food and herb shops and product samples was 237higher Product initiation after personal decision or upon recommendation of relatives and friends was also more 238important for other health products (see Table and 5) 239 2403.6 Pregnancy tests: purchase and advice 24184% of women had used a urinary pregnancy test to confirm pregnancy Half of these women bought the test in a 242public pharmacy, while grocery stores, supermarkets and online purchase accounted as other supply channels 243Remarkably, pharmacists did not provide any information in 43% of the cases Furthermore, the importance of folic 244acid intake was mentioned in only 14% of the situations More information about the pharmacist’s advice as 245perceived by the women is shown in Supplementary Material – 246 2473.7 Preconception lifestyle changes 248To investigate additional lifestyle changes besides preconception intake of folic acid, women were asked about their 249substance use before and during pregnancy Prior to pregnancy, alcohol use (64%) was more prevalent than smoking 250(12%) and use of illicit drugs (3%) 6% of pregnant women reported to use alcohol and/or cigarettes during the 251preceding week (see Table 6); 1% used both Women who used alcohol or smoked before pregnancy, mainly stopped 252after pregnancy diagnosis (78% and 83%, respectively) 7 253In general, 32% of women confirmed to have made preconception lifestyle changes, regardless of folic acid intake 254and substance use Half of them answered eating more fruits and vegetables, drinking more water, drinking less 255caffeine containing beverages (coffee, cola) or paying extra attention to what (not) to eat One-fourth of women 256reported doing more physical activity, while vaccine status was checked by 20% of the women 257 DISCUSSION 258In this study, we aimed to investigate health products’ and substance use among pregnant women visiting a tertiary 259hospital in Belgium First, we found that half of the pregnant women used at least one registered medicine during the 260preceding week, with 36% using a prescription medicine and 28% an OTC medicine Paracetamol, levothyroxine 261and antacids were the most frequently used medicines, thereby confirming previous findings for paracetamol and 262antacids.(4-6) The estimated prevalence of levothyroxine use, however, was four-fold higher than observed in other 263pregnancy cohorts(6, 7, 24, 25), likely due to the study setting and the clinical protocol with a low threshold of initiating 264treatment which was followed in the study period (TSH >2.5 mIU/L between and 11 weeks, TSH >3 from 12w 265onwards) Second, the prevalence of pregnancy vitamin use during the preceding week was 86% and increased to 26697% if the entire pregnancy was taken into account The high prevalence of multivitamin intake and vitamin D 267supplementation (≥60%) was in line with previous findings.(26, 27) Third, the high prevalence of thyroid hormone, iron, 268magnesium supplements and multivitamins increased the likelihood of drug-drug interactions due to concomitant 269intake These data should motivate HCPs to be vigilant for the use of drug combinations in this population, in order 270to prevent suboptimal maternal treatment With regard to safety aspects, the use of other health products also 271deserves our attention Health products such as essential oils or alcohol containing preparations have a negative 272benefit-risk ratio during pregnancy Although their use was rather limited, they were often started on personal 273initiative or suggested by family and friends and were commonly purchased via supermarkets, shops or received as 274product samples(13, 14) Therefore, HCPs should be aware that pregnant women might use and purchase inappropriate 275products without professional advice In the future, HCPs need to discuss the use of all kind of health products when 276counselling pregnant women 277 278Furthermore, we found that preconception intake of folic acid is still insufficient in Belgium, (26, 27) which calls HCPs 279and policy makers upon action Although a high prevalence of folic acid intake during the preceding week was 280observed, half of the women started too late and more than 25% of pregnant women did not use folic acid in the first 2814 weeks Since no increase in folic acid intake was observed over the last years, (26, 27) we can assume that recent 282initiatives, such as the establishment of an evidence-based website on preconception care in Belgium in 2015, (28) did 283not have sufficient positive impact on the preconception folic acid intake It is obvious that all HCPs involved in 284prenatal care should discuss the intake of folic acid, preferably during each contact with (pregnant) women To 285assure folic acid initiation before neural tube closure, community pharmacists have the opportunity to discuss folic 286acid when dispensing pregnancy tests, especially when women have not yet started it (29) In our cohort, folic acid was 287mentioned in only 14% of the pharmacy encounters related to pregnancy tests, which was in line with a previous 288pilot study.(30) As a result, less than 10% of women who used a urinary pregnancy test were informed about the 289importance of preconception folic acid when purchasing a test, assuming that other supply channels not provide 8 290any information about folic acid Surprisingly, preconception use of folic acid in ART users was also insufficient, 291despite frequent visits to the fertility center and supposed intensive follow-up This finding definitely needs further 292investigation and urges for strategies to tackle current challenges 293 294Other preconception opportunities that have been identified relate to alcohol use and smoking Although it has 295previously been shown that women perceive alcohol and cigarettes as most risky products during pregnancy (5), 296prevalence for alcohol use and smoking in our cohort was 6% Even though higher prevalences were found in other 297countries,(31-35) this finding is worrying Furthermore, most women stopped drinking alcohol and/or smoking only 298after pregnancy diagnosis, as shown earlier (36, 37) Poor changes in substance use prior to pregnancy might expose the 299fetus to teratogens during the most vulnerable weeks of pregnancy In addition, preconception changes in dietary 300habits barely occurred.(36, 38) Hence, preconception care should be further developed and implemented in Belgium 301Luckily, a recent study showed that reproductive-aged women in Belgium have interest in receiving more 302preconception care in the future.(39) 303 304Data were collected using a self-reporting survey Survey completion occured outside the direct supervision of an 305involved HCP, which might have prevented women from giving socially desirable answers Reliability of product 306information was pursued by incorporating an up-to-date, picture-based database of health products available in 307Belgium To ensure completeness of data collection, the main question about health products’ use was asked four 308times In addition, respondents were informed that individual answers would be encoded, thereby stimulating 309participants to disclose all applicable health products Finally, women were asked to report only the use of medicines 310and other health products during the last seven days, thereby limiting recall bias and maximizing correctness of 311prevalence estimates and type of products 312Some limitations should also be kept in mind when interpreting the findings The study was limited to women 313visiting a tertiary hospital Compared to general and pregnancy-related population data, study participants slighty 314differed with respect to age, highest degree of education and ART use before the current pregnancy (40-42) As 315medication use increases with age, overestimation of the prevalence of medication use during the preceding week is 316possible In contrast, highly educated women seem to have a higher threshold to use medicines during pregnancy (43), 317which in turn could have led to an underestimation of the prevalence Nonetheless, an underestimation of the total 318medication exposure during pregnancy is expected, as only medication use during the last week was studied With 319regard to preconception folic acid intake, the prevalence in the general population might be even lower, as the study 320findings indicated that folic acid intake increases with age and among women occupied in healthcare In this study, 321pregnant women who did not understand Dutch, French or English were excluded In the future, it would be 322interesting to study health products’ and substance use among these group of women From a fetal-maternal safety 323perspective, however, the study findings as described in the current paper are considered to be important for HCPs 324and policy makers involved in prenatal care within and outside Belgium 325 326 CONCLUSION 327Pregnant women visiting a tertiary hospital in Belgium frequently use medicines, pregnancy vitamins, and other 328health products Preconception lifestyle changes such as folic acid intake and alcohol and smoking cessation are 329poorly implemented These findings emphasize the importance of counselling on preconception lifestyle changes and 330on the safe use of health products during pregnancy Public campaigns and interventions are needed to improve 331preconception care and to improve HCPs’ counselling 332 333ETHICS STATEMENT 334Ethical approval was granted from the local Medical Ethics committee and the study was conducted in accordance 335with the declaration of Helsinki and applicable privacy requirements 336 337AKNOWLEDGEMENTS 338We want to thank the Faculty of Pharmaceutical Sciences and the Academic Foundation Leuven for supporting the 339research project We are also grateful to the midwives working at the consultation of the University Hospital of 340Leuven, masterstudents, Martial Luyts (statistician), and Medipim (database) for their contribution to data collection 341and analyses 342 343CONFLICT OF INTEREST 344The authors declare no conflict of interest 345 346AUTHORS’ CONTRIBUTION 347MC carried out data collection, data analysis and drafted the initial and final version of the manuscript All authors 348contributed to the study design and reviewed and approved the initial and final version of the manuscript 349 350 351 352 353 354 355 356 357 358 359 360 361 362 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450changes around the time of pregnancy: a cross-sectional study BMJ open 2016;6(5):e010233 45139 Goossens J, Delbaere I, Dhaenens C, Willems L, Van Hecke A, Verhaeghe S, et al Preconception-related 452needs of reproductive-aged women Midwifery 2016;33:64-72 45340 Devlieger R, Martens E, Martens G , Van Mol C, Cammu H Perinatal activities in Flanders, Belgium 2016 454Study Centre for Perinatal Epidemiology 2017 45541 Child and Family The child in Flanders, Belgium 2016; https://www.kindengezin.be/img/kiv2016.pdf 4562017 Accessed 22.04.2019 45742 Statbel Education and employment in Flanders, Belgium (2016); https://statbel.fgov.be/en 2017 Accessed 45822.04.2019 12 12 45943 Ceulemans M, Van Calsteren K, Allegaert K, Foulon V Beliefs about medicines and information needs 460among pregnant women visiting a tertiary hospital in Belgium Eur J Clin Pharm 2019 461 462 463 464 465TABLES 466 467 TABLE Socio-demographic characteristics of study participants (n=379) 468 469 Characteristics Number % 470 Age 40 18 237 81 32 5% 64% 22% 9% 1% Planning to breastfeed Yes No Don’t know yet 301 44 34 79% 12% 9% Pregnancy follow-up mainly by Obstetrician Midwife General practitioner 246 92 41 65% 24% 11% *Data obtained from hospital medical records 531 532 533 534 14 14 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 TABLE Prevalence of the most frequently used medicines during the preceding week (n=376) Most frequently used medicines during the preceding week Paracetamol (14%) Progesterone (4%) Levothyroxine (13%) Low molecular weight heparin (2%) Antacids (9%) Meclizine (2%) High dose oral iron (7%) Metoclopramide (2%) Low dose aspirin (6%) 10 Insulins (2%) 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 15 15 575 576 577 578 579 580 581 582 583 584 Advice by 585 Obstetrician 586 587 588 589 590 TABLE Counselling of health products during pregnancy Variables are expressed as % (number) within the respective health product’s category Registered medicines (n=321) 38% (121) Pregnancy vitamins (n=394) 27% (105) Other health products (n=304) 6% (17) General practitioner 34% (108) 29% (115) 14% (43) Another medical doctor 11% (36) 1% (3) 3% (9) Personal decision 9% (28) 25% (98) 42% (127) Pharmacist 5% (15) 5% (18) 13% (39) Midwife 4% (12) 5% (18) 2% (6) Relative/partner