Thérapie 2014 Janvier-Février; 69 (1): 65–69 DOI: 10.2515/therapie/2014009
PHARMACOEPIDEMIOLOGY
© 2014 Société Française de Pharmacologie et de Thérapeutique
Nordic Databases to Evaluate Medications in Pregnancy Helle Kieler Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden Text received August 8th, 2013; accepted September 17th, 2013
Keywords: pregnancy; drugs; Nordic health registers
Abstract – The objective of this review is to describe the possibilities to assess drugs used in pregnancy by means of the Nordic health registers. The Nordic countries comprise five countries: Denmark, Finland, Iceland, Norway and Sweden and have a total population of 25 million. All five countries have in their national health registers for many years recorded information concerning all births, cancer diagnoses, hospital contacts, causes of death and dispensed drugs. The registers can be used for studying drugs dispensed during pregnancy and though most previous studies focused on risks of congenital abnormalities, other health consequences of maternal medication can also be assessed.
Mots clés : grossesse ; médicaments ; registres nordiques de santé
Résumé – Les bases de données des pays nordiques pour l’évaluation des médicaments pendant la grossesse. L’objectif de cette étude est de décrire les possibilités d’évaluer les médicaments utilisés pendant la grossesse à l’aide des registres de santé nordiques. Les pays nordiques sont composés de cinq pays : Danemark, Finlande, Islande, Norvège et Suède et ont une population totale de 25 millions d’habitants. Les cinq pays ont enregistré dans leurs registres nationaux de santé, depuis de nombreuses années, des informations concernant toutes les naissances, les diagnostics de cancer, les contacts hospitaliers, les causes de décès et les médicaments distribués. Les registres peuvent être utilisés pour l’étude des médicaments dispensés pendant la grossesse et si la plupart des études antérieures ont porté sur les risques d’anomalies congénitales, d’autres conséquences sur la santé de la mère suite à la prise de médicaments peuvent également être évaluées.
Abbreviations: see end of article.
1. Introduction The Nordic countries have for many decades collected information from health care facilities concerning births, diseases and deaths.[1] The information is stored in various national health registers and information on prescribed drugs dispensed at pharmacies is recorded in specific drug registers.[2] The registers are employed by the national authorities; the register data is of high quality and covers the whole population in each country. All the registers include a 10 or 11 digit code, the personal identification number (PIN) assigned to each Nordic inhabitant and it is possible to link information from different registers.[3] By means of the health registers information on drug exposure during pregnancy can be obtained for all individuals living in the Nordic countries.
from around 300 000 living in Iceland to 9.5 million in Sweden. The Nordic countries all have public health care systems, which facilitate obtaining information to the registers. Each country has its own PINs, though for individuals who have moved between the Nordic countries it is possible to link a PIN assigned in one country with a PIN from the other country. The health care systems, the construction of and the contents in the national registers are similar in the Nordic countries. Therefore and considering the small populations in each of the Nordic countries it is inevitable to use information from several countries when studying rare exposures and rare outcomes, such as consequences of drug exposure during pregnancy.[4] Almost 300 000 infants are born each year in the Nordic countries and information concerning these infants and their mothers has been recorded in the birth registers for more than two decades.
3. The registers
2. Nordic countries The five Nordic countries include Denmark, Finland, Iceland, Norway and Sweden. The total population is approximately 25 million,
The Nordic national health registers include the birth registers, the cancer registers, the patient registers, the cause of death registers
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and the drug registers.[1,5] Each country also has population registers with socio-demographic information and several disease specific registers.[6-8] Reporting to the national health registers is mandatory and regulated by national laws, whereas reporting to the disease specific registers is optional. The parliaments in the Nordic countries have on behalf of their populations given informed consent to be included in the national registers and the information recorded can be used for research purposes. The administration of the registers varies from one register holder in one country to several in others and so does the way of obtaining the information for research purposes.
4. Birth registers The Nordic birth registers were established shortly after the association between thalidomide exposure during pregnancy and limb malformations in the offspring had been revealed.[9-11] The major purpose with establishing national birth registers with mandatory reporting was to avoid a recurrence of this tragedy. The Norwegian medical birth register, which was established in 1967 was the first Nordic birth register and it was shortly followed by birth registers in Denmark and Sweden.[12-16] In 1987 also Finland and Iceland got their birth registers.[11] The registers include prospectively collected information concerning maternal socio-demographic characteristics, pregnancy, delivery, and neonatal data on all live births and stillbirths born gestational week 22 or later.[11] The contents of the registers have changed during the years opening up for new variables to be included, but also for logistical reasons, stopping reporting of variables, which were previously recorded.[17] Despite the major reason for starting the birth registers was the thalidomide catastrophe, none of the registers did at start include information on drug intake during pregnancy. The only Nordic birth register, which now take in drug information is the Swedish medical birth register, and the possibility to report drugs used during pregnancy occurred not until 1994, more than twenty years after starting the register.[18] In the Swedish medical birth register the information on drugs is self-reported use, which is to be obtained throughout pregnancy. The reporting starts at first visit to antenatal care, where the midwife records all drugs used during pregnancy, including information on prescribed drugs, over-the-counter (OTC) drugs, natural remedies, and homeopathics. At each antenatal visit, the midwife and the attending doctor update information on drug use in the standardized record. The lack of information on drugs in the other birth registers is compensated by the possibility to link information in the birth registers with that included in the drug registers.[18-21]
5. Drug registers Of the Nordic national health registers the drug registers are the most recent.[22] The oldest drug registers are those in Finland and
© Société Française de Pharmacologie et de Thérapeutique
Denmark, which started including individual information on filled prescriptions in 1994 and 1995, respectively.[23,24] Norway, Iceland and Sweden got their drug registers almost ten years later and Sweden was the last to establish such a register in 2005.[25,26] The reasons for establishing drug registers varied between the Nordic countries, from a statistical instrument simplifying the administration of drug reimbursement to inspection of off-label prescribing of opioids. Despite the different motivations for starting drug registers, all Nordic countries opened up for the possibility to use the information in the registers for research purposes. Except for the drug register in Finland, the drug registers include information on all dispensed drugs. In Finland, only reimbursed drugs are included. The drug registers include data on the dispensed item, substance, brand name, and formulation together with date of dispensing. All drugs are classified according to the World health organization (WHO), anatomical therapeutic chemical (ATC) classification.
6. Quality of information in the registers The quality of health data registers is crucial for their usefulness in research.[1,17,27] In a previous study we compared information on self-reported drug use as recorded in the Swedish medical birth register with that on dispensed drugs during pregnancy in the Swedish prescribed drug register.[18] We found that data on drug use in the Swedish medical birth register is more complete from early pregnancy than that obtained from later in pregnancy. Also, the agreement between drug use registered in the Swedish medical birth register and the information in the Swedish prescribed drug register is much better for drugs used for chronic conditions than for drugs used more occasionally, such as antibiotics. Similar findings were reported in studies from Denmark and Norway comparing information in the drug registers with that obtained from large surveys on pregnancies.[19,28] Whether it is the information on self-reported use as recorded in the Swedish medical birth register or the information on dispensed drugs as recorded in the drug register, which is closest to the true exposure remains to be solved. The great advantage is to have information collected in different ways and for some drug exposures the combined information might be most valuable. It should also be noted that the drug registers in contrast to the drug information in the Swedish medical birth register do not include information on drugs administered in hospitals, OTC drugs, natural remedies or homeopathics. Antibiotics given to pregnant women in connection with hospital admissions and antenatal corticosteroids in case of imminent preterm delivery are examples of drugs, which are not covered by the drug registers. In the patient registers in Denmark and Sweden, there is a possibility to record in hospital drug administration by a procedure code together with an ATCcode, a possibility, which is used increasingly and which opens up for the ability to obtain a more complete information on drug exposure.
Thérapie 2014 Janvier-Février; 69 (1)
Pregnancy and Drugs in Nordic Registers
7. Previous research on drugs during pregnancy Thousands of scientific articles have been published using information from the Nordic birth registers and use of information from the drug registers in research studies is evolving rapidly.[4,6,2938] Considering the longer availability of register data on drugs in Denmark, most studies, as well descriptive as analytic, on drugs during pregnancy have been conducted in Denmark. Descriptive studies on use of prescribed drugs during pregnancy among women giving birth and recorded in the birth registers have been reported from Finland, Norway and Sweden.[18,19,39] These studies confirmed findings from similar studies in France and other European countries that drugs are frequently used by pregnant women, but also that potentially harmful drugs are seldom used.[40-44] Information concerning long-term effects on the off-spring from exposures during fetal life and health consequences for chronically ill women, abstaining from their medication during pregnancy is still sparse. In this context, data from the Nordic national health registers will be very helpful, considering their possibilities for complete follow-up on all inhabitants.[30,35] Most studies on drugs during pregnancy and conducted in the Nordic countries have, in accordance with the major aims of the birth registers, mainly focused on associations between maternal exposure to specific drugs and subsequent risks of congenital anomalies.[29] Considering that specific congenital anomalies are rare outcomes, regrettably, only few studies took the advantage of using data from more than one country to address their research questions. The possibility to merge information from the national registers in all the Nordic countries, when assessing risks of adverse outcomes in the infants in association with use of serotonin reuptake inhibitors (SRIs) during pregnancy has recently been shown.[4,34] Though both funding and privacy legislations are major hurdles, the possibilities and willingness to perform multinational studies will hopefully improve in the future.[45]
8. Ethical concerns As the registers contain sensitive data on individuals there is legitimate concern about their confidentiality and the ethics of the registers are repeatedly discussed. The procedure for obtaining register information for research purposes varies between the Nordic countries, from no requirements of study specific ethical approvals to detailed applications and approvals from all various register holders. The shared attribute of no requirement of informed consent is, however, a key stone for the richness of data in the Nordic national registers. Informed consent approvals would not be possible for economical or procedural reasons in connection with recording of data. Though Nordic citizens, in general, might not be aware of which data is kept in the national registers, those included in the registers should, however, in connection with health care contacts be informed that certain information about them is forwarded to the registers.[46]
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In contrast to information recorded in clinical trials the information recorded in the national registers cannot be withdrawn by the individual, which further strengthens the requirements of cautious data handling. The recent debate concerning introduction of general regulations for individual data protection within the European union created much concern among Nordic register researchers as restrictions concerning recording and attaining of data was foreseen. The great possibilities to improve public health in a rational way through pre-collected information, which is obtained in well managed and controlled national registers should, however, prevail over the minimal risks of violating the integrity of an individual. Researchers using information from the national registers should acknowledge the dilemma between benefits for the public in general and the individual’s rights to not reveal sensitive information about him or herself. Obviously, researchers using information from the national registers must take all measures to manage this opportunity and responsibility in an ethical correct manner.
9. Limitations The birth registers include pregnancies resulting in a live birth or a still birth after at least gestational week 22. In Finland, Denmark and Norway the registers also include information on terminated pregnancies, but the information is not complete, mainly because less successful pregnancies might not be recognized and therefore never reported.[47] In Sweden, individual information on terminated pregnancies is not recorded for integrity reasons. Information on congenital malformations is recorded in the Nordic birth registers, except for Finland, which has a specific malformation register. The data from the Finnish malformation register is linked to information from the other registers in a database at the authorities.[20,48] The linkage of information from several registers can be time consuming and this together with the lag times for some registers means that the most recent information will not be possible to obtain. Other limitations, when using register information for research purposes is that the information sometimes is not sufficiently detailed and the number of variables is limited. Consequently, it is harder to control for confounders related to patient characteristics.
10. Conclusions The knowledge derived from research based on the Nordic birth registers has improved health in the pregnant population, reduced perinatal morbidity and mortality and increased our knowledge of the factors, which influence pregnancy and birth. The Nordic birth registers include information on several million of infants and their mothers, and information on drug exposure during pregnancy can be obtained by linking information from the birth registers with that recorded in the drug registers. This option of data linkage between birth and drug registers has been possible in all the Nordic countries
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for 8 years, and information on drug exposure in fetal life is now available for almost 2.5 million children. As exposure to potential harmful drugs during pregnancy and adverse infant outcomes are rare outcomes, this impressive figure of 2.5 million might not always be sufficient to assess safety of drug use in pregnancy. For this reason and to improve the generalizability of the results further international collaborations are welcomed. Conflicts of interests. None. Abbreviations. ATC: anatomical therapeutic chemical; OTC drugs: over-the-counter drugs; PIN: personnal identification number; SRIs: serotonin reuptake inhibitors; WHO: World health organization.
References
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10. Gissler M, Louhiala P, Hemminki E. Nordic medical birth registers in epidemiological research. Eur J Epidemiol 1997; 13(2): 169-75 11. Gissler M. Registration of births and induced abortions in the Nordic countries. Finnish yearbook of population research. 2010: 171-8, http://vaestoliitto-fi-bin.directo.fi/@Bin/ f8bf3e6dcb5580763b5363e8fd4b2cfe/1377153041/application/pdf/ 850175/YB%202010_Gissler,%20pp.171%13178.pdf Accessed November 18th, 2013 (8 pages) 12. Irgens LM. The Medical birth registry of Norway. Epidemiological research and surveillance throughout 30 years. Acta Obstet Gynecol Scand 2000; 79(6): 435-9 13. Sørensen HT, Sabroe S, Rothman KJ, et al. Birth weight and length as predictors for adult height. Am J Epidemiol 1999; 149(8): 726-9
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20. Artama M, Gissler M, Malm H, et al. Nationwide register-based surveillance system on drugs and pregnancy in Finland 1996-2006. Pharmacoepidemiol Drug Saf 2011; 20(7): 729-38 21. Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA 2010; 304(8): 859-66
25. Norwegian prescription database, http://www.fhi.no/eway/default.aspx?pid=240&trg=Main_6664&Main_6664= 6898:0:25,7843:1:0:0:::0:0 Accessed November 18th, 2013 26. Socialstyrelsen. Swedish national board of health and welfare. Fyra år med läkemedelsregistret. Publication celebrating the fourth anniversary of the Swedish prescribed drug register. National board of health and welfare. Stockholm, 2009, http://www.socialstyrelsen.se Accessed November 18th, 2013 27. Cnattingius S, Ericson A, Gunnarskog J, et al. A quality study of a medical birth registry. Scand J Soc Med 1990; 18(2): 143-8 28. Olesen C, Søndergaard C, Thrane N, et al. Do pregnant women report use of dispensed medications? Epidemiology 2001; 12(5): 497-501 29. Wettermark B, Zoëga H, Furu K, et al. The Nordic prescription databases as a resource for pharmacoepidemiological research – a literature review. Pharmacoepidemiol Drug Saf 2013; 22(7): 691-9 30. Henningsen AK, Romundstad LB, Gissler M, et al. Infant and maternal health monitoring using a combined Nordic database on ART and safety. Acta Obstet Gynecol Scand 2011; 90(7): 683-91
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31. Hjalgrim LL, Rostgaard K, Hjalgrim H, et al. Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland. J Natl Cancer Inst 2004; 96(20): 1549-56 32. Laine K, Rotvold W, Staff AC. Are obstetric anal sphincter ruptures preventable?-- large and consistent rupture rate variations between the Nordic countries and between delivery units in Norway. Acta Obstet Gynecol Scand 2013; 92(1): 94-100 33. Rom AL, Mortensen LH, Cnattingius S, et al. A comparative study of educational inequality in the risk of stillbirth in Denmark, Finland, Norway and Sweden 1981-2000. J Epidemiol Community Health 2012; 66(3): 240-6 34. Stephansson O, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA 2013; 309(1): 48-54 35. Stephansson O, Wahnström C, Pettersson A, et al. Perinatal risk factors for childhood testicular germ-cell cancer: a Nordic population-based study. Cancer Epidemiol 2011; 35(6): e100-4 36. Cnattingius S, Villamor E, Johansson S, et al. Maternal obesity and risk of preterm delivery. JAMA 2013; 309(22): 2362-70 37. Johansson AL, Dickman PW, Kramer MS, et al. Maternal smoking and infant mortality: does quitting smoking reduce the risk of infant death? Epidemiology 2009 Jul; 20(4): 590-7 38. Källén B, Finnström O, Lindam A, et al. Cancer risk in children and young adults conceived by in vitro fertilization. Pediatrics 2010; 126(2): 270-6 39. Malm H, Martikainen J, Klaukka T, et al. Prescription drugs during pregnancy and lactation – a Finnish register-based study. Eur J Clin Pharmacol 2003; 59(2): 127-33 40. Bakker MK, Jentink J, Vroom F, et al. Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands. BJOG 2006; 113(5): 559-68
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41. Bjørn AM, Nørgaard M, Hundborg HH, et al. Use of prescribed drugs among primiparous women: an 11-year population-based study in Denmark. Clin Epidemiol 2011; 3: 149-56 42. Crespin S, Bourrel R, Hurault-Delarue C, et al. Drug prescribing before and during pregnancy in south west France: a retrolective study. Drug Saf 2011; 34(7): 595-604 43. Egen-Lappe V, Hasford J. Drug prescription in pregnancy: analysis of a large statutory sickness fund population. Eur J Clin Pharmacol 2004; 60(9): 659-66 44. Irvine L, Flynn RW, Libby G, et al. Drugs dispensed in primary care during pregnancy: a record-linkage analysis in Tayside, Scotland. Drug Saf 2010; 33(7): 593-604 45. Petridou ET, Sergentanis TN, Panagopoulou P, et al. In vitro fertilization and risk of childhood leukemia in Greece and Sweden. Pediatr Blood Cancer 2012; 58(6): 930-6 46. Hultman C, Lindgren A, Hansson M, et al. Ethical issues in cancer register follow-up of hormone treatment in adolescence. Public Health Ethics 2009; 2(1): 30-6 47. Buss L, Tolstrup J, Munk C, et al. Spontaneous abortion: a prospective cohort study of younger women from the general population in Denmark. Validation, occurrence and risk determinants. Acta Obstet Gynecol Scand 2006; 85(4): 467-75 48. Malm H, Artama M, Brown AS, et al. Infant and childhood neurodevelopmental outcomes following prenatal exposure to selective serotonin reuptake inhibitors: overview and design of a Finnish register-based study (FinESSI). BMC Psychiatry 2012; 12: 217 Correspondence and offprints: Helle Kieler, Centre for Pharmacoepidemiology, Karolinska Institutet, T2, Karolinska University Hospital, SE 171 76 Stockholm, Sweden. E-mail: [email protected]
Thérapie 2014 Janvier-Février; 69 (1)
PHARMACOEPIDEMIOLOGY
© 2014 Société Française de Pharmacologie et de Thérapeutique
Nordic Databases to Evaluate Medications in Pregnancy Helle Kieler Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden Text received August 8th, 2013; accepted September 17th, 2013
Keywords: pregnancy; drugs; Nordic health registers
Abstract – The objective of this review is to describe the possibilities to assess drugs used in pregnancy by means of the Nordic health registers. The Nordic countries comprise five countries: Denmark, Finland, Iceland, Norway and Sweden and have a total population of 25 million. All five countries have in their national health registers for many years recorded information concerning all births, cancer diagnoses, hospital contacts, causes of death and dispensed drugs. The registers can be used for studying drugs dispensed during pregnancy and though most previous studies focused on risks of congenital abnormalities, other health consequences of maternal medication can also be assessed.
Mots clés : grossesse ; médicaments ; registres nordiques de santé
Résumé – Les bases de données des pays nordiques pour l’évaluation des médicaments pendant la grossesse. L’objectif de cette étude est de décrire les possibilités d’évaluer les médicaments utilisés pendant la grossesse à l’aide des registres de santé nordiques. Les pays nordiques sont composés de cinq pays : Danemark, Finlande, Islande, Norvège et Suède et ont une population totale de 25 millions d’habitants. Les cinq pays ont enregistré dans leurs registres nationaux de santé, depuis de nombreuses années, des informations concernant toutes les naissances, les diagnostics de cancer, les contacts hospitaliers, les causes de décès et les médicaments distribués. Les registres peuvent être utilisés pour l’étude des médicaments dispensés pendant la grossesse et si la plupart des études antérieures ont porté sur les risques d’anomalies congénitales, d’autres conséquences sur la santé de la mère suite à la prise de médicaments peuvent également être évaluées.
Abbreviations: see end of article.
1. Introduction The Nordic countries have for many decades collected information from health care facilities concerning births, diseases and deaths.[1] The information is stored in various national health registers and information on prescribed drugs dispensed at pharmacies is recorded in specific drug registers.[2] The registers are employed by the national authorities; the register data is of high quality and covers the whole population in each country. All the registers include a 10 or 11 digit code, the personal identification number (PIN) assigned to each Nordic inhabitant and it is possible to link information from different registers.[3] By means of the health registers information on drug exposure during pregnancy can be obtained for all individuals living in the Nordic countries.
from around 300 000 living in Iceland to 9.5 million in Sweden. The Nordic countries all have public health care systems, which facilitate obtaining information to the registers. Each country has its own PINs, though for individuals who have moved between the Nordic countries it is possible to link a PIN assigned in one country with a PIN from the other country. The health care systems, the construction of and the contents in the national registers are similar in the Nordic countries. Therefore and considering the small populations in each of the Nordic countries it is inevitable to use information from several countries when studying rare exposures and rare outcomes, such as consequences of drug exposure during pregnancy.[4] Almost 300 000 infants are born each year in the Nordic countries and information concerning these infants and their mothers has been recorded in the birth registers for more than two decades.
3. The registers
2. Nordic countries The five Nordic countries include Denmark, Finland, Iceland, Norway and Sweden. The total population is approximately 25 million,
The Nordic national health registers include the birth registers, the cancer registers, the patient registers, the cause of death registers
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and the drug registers.[1,5] Each country also has population registers with socio-demographic information and several disease specific registers.[6-8] Reporting to the national health registers is mandatory and regulated by national laws, whereas reporting to the disease specific registers is optional. The parliaments in the Nordic countries have on behalf of their populations given informed consent to be included in the national registers and the information recorded can be used for research purposes. The administration of the registers varies from one register holder in one country to several in others and so does the way of obtaining the information for research purposes.
4. Birth registers The Nordic birth registers were established shortly after the association between thalidomide exposure during pregnancy and limb malformations in the offspring had been revealed.[9-11] The major purpose with establishing national birth registers with mandatory reporting was to avoid a recurrence of this tragedy. The Norwegian medical birth register, which was established in 1967 was the first Nordic birth register and it was shortly followed by birth registers in Denmark and Sweden.[12-16] In 1987 also Finland and Iceland got their birth registers.[11] The registers include prospectively collected information concerning maternal socio-demographic characteristics, pregnancy, delivery, and neonatal data on all live births and stillbirths born gestational week 22 or later.[11] The contents of the registers have changed during the years opening up for new variables to be included, but also for logistical reasons, stopping reporting of variables, which were previously recorded.[17] Despite the major reason for starting the birth registers was the thalidomide catastrophe, none of the registers did at start include information on drug intake during pregnancy. The only Nordic birth register, which now take in drug information is the Swedish medical birth register, and the possibility to report drugs used during pregnancy occurred not until 1994, more than twenty years after starting the register.[18] In the Swedish medical birth register the information on drugs is self-reported use, which is to be obtained throughout pregnancy. The reporting starts at first visit to antenatal care, where the midwife records all drugs used during pregnancy, including information on prescribed drugs, over-the-counter (OTC) drugs, natural remedies, and homeopathics. At each antenatal visit, the midwife and the attending doctor update information on drug use in the standardized record. The lack of information on drugs in the other birth registers is compensated by the possibility to link information in the birth registers with that included in the drug registers.[18-21]
5. Drug registers Of the Nordic national health registers the drug registers are the most recent.[22] The oldest drug registers are those in Finland and
© Société Française de Pharmacologie et de Thérapeutique
Denmark, which started including individual information on filled prescriptions in 1994 and 1995, respectively.[23,24] Norway, Iceland and Sweden got their drug registers almost ten years later and Sweden was the last to establish such a register in 2005.[25,26] The reasons for establishing drug registers varied between the Nordic countries, from a statistical instrument simplifying the administration of drug reimbursement to inspection of off-label prescribing of opioids. Despite the different motivations for starting drug registers, all Nordic countries opened up for the possibility to use the information in the registers for research purposes. Except for the drug register in Finland, the drug registers include information on all dispensed drugs. In Finland, only reimbursed drugs are included. The drug registers include data on the dispensed item, substance, brand name, and formulation together with date of dispensing. All drugs are classified according to the World health organization (WHO), anatomical therapeutic chemical (ATC) classification.
6. Quality of information in the registers The quality of health data registers is crucial for their usefulness in research.[1,17,27] In a previous study we compared information on self-reported drug use as recorded in the Swedish medical birth register with that on dispensed drugs during pregnancy in the Swedish prescribed drug register.[18] We found that data on drug use in the Swedish medical birth register is more complete from early pregnancy than that obtained from later in pregnancy. Also, the agreement between drug use registered in the Swedish medical birth register and the information in the Swedish prescribed drug register is much better for drugs used for chronic conditions than for drugs used more occasionally, such as antibiotics. Similar findings were reported in studies from Denmark and Norway comparing information in the drug registers with that obtained from large surveys on pregnancies.[19,28] Whether it is the information on self-reported use as recorded in the Swedish medical birth register or the information on dispensed drugs as recorded in the drug register, which is closest to the true exposure remains to be solved. The great advantage is to have information collected in different ways and for some drug exposures the combined information might be most valuable. It should also be noted that the drug registers in contrast to the drug information in the Swedish medical birth register do not include information on drugs administered in hospitals, OTC drugs, natural remedies or homeopathics. Antibiotics given to pregnant women in connection with hospital admissions and antenatal corticosteroids in case of imminent preterm delivery are examples of drugs, which are not covered by the drug registers. In the patient registers in Denmark and Sweden, there is a possibility to record in hospital drug administration by a procedure code together with an ATCcode, a possibility, which is used increasingly and which opens up for the ability to obtain a more complete information on drug exposure.
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Pregnancy and Drugs in Nordic Registers
7. Previous research on drugs during pregnancy Thousands of scientific articles have been published using information from the Nordic birth registers and use of information from the drug registers in research studies is evolving rapidly.[4,6,2938] Considering the longer availability of register data on drugs in Denmark, most studies, as well descriptive as analytic, on drugs during pregnancy have been conducted in Denmark. Descriptive studies on use of prescribed drugs during pregnancy among women giving birth and recorded in the birth registers have been reported from Finland, Norway and Sweden.[18,19,39] These studies confirmed findings from similar studies in France and other European countries that drugs are frequently used by pregnant women, but also that potentially harmful drugs are seldom used.[40-44] Information concerning long-term effects on the off-spring from exposures during fetal life and health consequences for chronically ill women, abstaining from their medication during pregnancy is still sparse. In this context, data from the Nordic national health registers will be very helpful, considering their possibilities for complete follow-up on all inhabitants.[30,35] Most studies on drugs during pregnancy and conducted in the Nordic countries have, in accordance with the major aims of the birth registers, mainly focused on associations between maternal exposure to specific drugs and subsequent risks of congenital anomalies.[29] Considering that specific congenital anomalies are rare outcomes, regrettably, only few studies took the advantage of using data from more than one country to address their research questions. The possibility to merge information from the national registers in all the Nordic countries, when assessing risks of adverse outcomes in the infants in association with use of serotonin reuptake inhibitors (SRIs) during pregnancy has recently been shown.[4,34] Though both funding and privacy legislations are major hurdles, the possibilities and willingness to perform multinational studies will hopefully improve in the future.[45]
8. Ethical concerns As the registers contain sensitive data on individuals there is legitimate concern about their confidentiality and the ethics of the registers are repeatedly discussed. The procedure for obtaining register information for research purposes varies between the Nordic countries, from no requirements of study specific ethical approvals to detailed applications and approvals from all various register holders. The shared attribute of no requirement of informed consent is, however, a key stone for the richness of data in the Nordic national registers. Informed consent approvals would not be possible for economical or procedural reasons in connection with recording of data. Though Nordic citizens, in general, might not be aware of which data is kept in the national registers, those included in the registers should, however, in connection with health care contacts be informed that certain information about them is forwarded to the registers.[46]
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In contrast to information recorded in clinical trials the information recorded in the national registers cannot be withdrawn by the individual, which further strengthens the requirements of cautious data handling. The recent debate concerning introduction of general regulations for individual data protection within the European union created much concern among Nordic register researchers as restrictions concerning recording and attaining of data was foreseen. The great possibilities to improve public health in a rational way through pre-collected information, which is obtained in well managed and controlled national registers should, however, prevail over the minimal risks of violating the integrity of an individual. Researchers using information from the national registers should acknowledge the dilemma between benefits for the public in general and the individual’s rights to not reveal sensitive information about him or herself. Obviously, researchers using information from the national registers must take all measures to manage this opportunity and responsibility in an ethical correct manner.
9. Limitations The birth registers include pregnancies resulting in a live birth or a still birth after at least gestational week 22. In Finland, Denmark and Norway the registers also include information on terminated pregnancies, but the information is not complete, mainly because less successful pregnancies might not be recognized and therefore never reported.[47] In Sweden, individual information on terminated pregnancies is not recorded for integrity reasons. Information on congenital malformations is recorded in the Nordic birth registers, except for Finland, which has a specific malformation register. The data from the Finnish malformation register is linked to information from the other registers in a database at the authorities.[20,48] The linkage of information from several registers can be time consuming and this together with the lag times for some registers means that the most recent information will not be possible to obtain. Other limitations, when using register information for research purposes is that the information sometimes is not sufficiently detailed and the number of variables is limited. Consequently, it is harder to control for confounders related to patient characteristics.
10. Conclusions The knowledge derived from research based on the Nordic birth registers has improved health in the pregnant population, reduced perinatal morbidity and mortality and increased our knowledge of the factors, which influence pregnancy and birth. The Nordic birth registers include information on several million of infants and their mothers, and information on drug exposure during pregnancy can be obtained by linking information from the birth registers with that recorded in the drug registers. This option of data linkage between birth and drug registers has been possible in all the Nordic countries
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for 8 years, and information on drug exposure in fetal life is now available for almost 2.5 million children. As exposure to potential harmful drugs during pregnancy and adverse infant outcomes are rare outcomes, this impressive figure of 2.5 million might not always be sufficient to assess safety of drug use in pregnancy. For this reason and to improve the generalizability of the results further international collaborations are welcomed. Conflicts of interests. None. Abbreviations. ATC: anatomical therapeutic chemical; OTC drugs: over-the-counter drugs; PIN: personnal identification number; SRIs: serotonin reuptake inhibitors; WHO: World health organization.
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