- Email: [email protected]
Nine months that last a lifetime. Experience from the Danish National Birth Cohort and lessons learned
International Journal of Hygiene and Environmental Health 215 (2012) 142–144
Contents lists available at SciVerse ScienceDirect
International Journal of Hygiene and Environmental Health journal homepage: www.elsevier.de/ijheh
Short communication
Nine months that last a lifetime. Experience from the Danish National Birth Cohort and lessons learned Jørn Olsen ∗ Aarhus University, Department of Epidemiology, School of Public Health, Bartholins Allé 2, DK-8000 Aarhus C, Denmark
a r t i c l e
i n f o
Keywords: Pregnancy cohorts Life course epidemiology Fetal programming Follow up attrition Project coordination
a b s t r a c t A growing body of evidence indicates that antenatal care should focus not only on preventing perinatal complications but needs to see the early phase of life as important for a number of adult diseases as well. Most of the research comes from animal studies, since cohorts starting early in life that include biomarkers and have long term follow-up are few, the best known being the National Collaborative Perinatal Project (1959–1974) where only a part of the cohort are being followed (www.birthcohorts.net). Many cohorts are, however, in the planning phase, and the paper provides ten suggestions/recommendations for principal investigators of new or recently established cohorts. © 2011 Elsevier GmbH. All rights reserved.
Introduction Much has been achieved since Forsdahl, Lucas and Barker launched the idea about “fetal programming” or “early origin” of chronic diseases. The role of social conditions, nutrition or fetal growth was key in this phase, suggesting that poor social conditions, impaired fetal growth or lack of proper nutrition early in life might increase the risk of chronic diseases later in life, especially diabetes and cardiovascular diseases (Forsdahl, 1978; Barker, 1990; Gluckman and Hanson, 2006; Lucas, 1991, 1998). Since then many have shown that fetal growth is an important predictor of some chronic diseases that manifest themselves later in life, but the causal implications are still unsettled. Other results indicate that many other exposures early in life, like stress, infections or environmental exposures may have longlasting health effects (Li et al., 2010a, 2010b; Virk et al., 2010), and many disease endpoints are of interest, like mental disorders, cancers, immune diseases and more (Arai and Feig, 2010; Barr et al., 1990; Lumey et al., 2010; Nahmias et al., 2006; St Clair et al., 2005; Sun et al., 2008). There is substantial empirical evidence to support building up an infrastructure for studying the early origin of chronic diseases, especially in the light of the new knowledge about epigenetic modifications of gene expression. We know now that environmental factors may change gene expression through epigenetic mechanisms, and that may modify genetic environmental causes of disease. These epigenetic changes may take place throughout life but are expected to have more impact during fetal life and in early
∗ Tel.: +45 8942 6085; fax: +45 8613 1580. E-mail address: [email protected] 1438-4639/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijheh.2011.10.015
childhood. This new knowledge provides a plausible mechanism for how early exposures may have long-lasting health effects and provides new hopes for disease prevention, even for diseases which were previously believed to be of genetic origin. Furthermore, laboratory facilities and technologies are available for handling large-scale data sources. Gene mapping technologies open up for large-scale screening of millions of gene variants, soon probably full genome sequencing, and the technologies for studying epigenetic changes are getting better and better. What is still lacking are large scale population based cohorts which allow for long-term followup with good attrition. It is important that we set up studies that can identify preventable causes of disease and start as early in life as possible, and they should aim to include (prospective) data from conception to death. In the following, experience from the Danish National Birth Cohort (DNBC) will be presented. The DNBC, a short description The DNBC started recruitment of pregnant women in Denmark in 1996 and by 2002 included data from about 100,000 pregnancies. The objectives of the DNBC were to establish a large scale database with open access that could provide information on modifiable determinants of diseases in childhood and in adult life. The aim is to follow the cohort from conception to death. Details on the project can be found at www.dnbc.dk, but in short: The aim was to recruit pregnant women as early as possible in pregnancy, at best before conception. The best we could do was to recruit women when they came to their first pregnancy visit, which in Denmark is provided by their general practitioner (GP) around gestational week 6–12. At this visit, the GPs who participated in the study (about half of the GPs in the country) provided the
J. Olsen / International Journal of Hygiene and Environmental Health 215 (2012) 142–144
consent form and the background description of the study also called “Better Health for Mother and Child”. At this visit, a blood sample was taken to the study biobank after oral consent. The sample was stored with personal identification if written consent was received by mail. About 60% of the invited women mailed a signed form to the study center. A second blood sample was taken by the GP in the second trimester, and a blood sample from the child (umbilical cord) was taken by midwives shortly after delivery. All blood samples were sent by regular mail to the State Serum Institute in Copenhagen and processed there. This delay in processing blood samples and freezing will be OK for most time stable components in blood but not for other components like certain cytokines, etc. Data on lifestyle factors and environmental exposures were collected by medical questionnaires, computer assisted interviews (CATI) and, more recently, by using web-based questionnaires. We used two mailed questionnaires and 2 CATIs during pregnancy. After the delivery we conducted CATIs at 6 and 18 months, and we used mailed questionnaires or web-based questionnaires in the 7 years follow-up. In the 11 years follow-up, only web-based questionnaires are used at present. We have an ongoing follow-up for all participants based on linkage to existing population based research registers where we e.g. record all inpatient or outpatient contact to all Danish hospitals. We can also include data on redeemed prescribed medicine, changes in social conditions and much more based on linkage to registers established for administrative purposes. Endpoints in this study will therefore come from routine diagnosing in hospitals as reported to the national hospital register or some of the clinical databases, use of prescribed drugs or ad hoc data recorded at one of the follow up points (at present, 6 months, 18 months, 7 years and 11 years postpartum). Although response rates to data collection rounds that involve participants’ active collaboration are 50–70%, very few use their option to leave the study. Most participants accept to be invited for new data collection rounds. More information on the DNBC is available in our descriptive papers (Olsen et al., 2001) or on the website that also provides a reference to all publications based on the cohort data (www.dnbc.dk).
Lessons learned and 10 recommendations for further pregnancy cohort planners 1. Plan for long-term follow-up and make sure to have a budget to cover basic maintenance and running costs; contact to participants, data documentation, data cleaning and follow-up of participants. Like biologists, physicists and others need laboratories and machines, epidemiologists need data, and cohorts are part of our infrastructure. Do not underestimate these running costs. 2. Start data collection as early as possible. The time period of organogenesis is mainly over after 3 months of gestation. Make such as much data as possible is collected prospectively, before the occurrence of the endpoint of interest. Focus on data that cannot be recalled back in time; especially data on diet, medicine intake and short-term health problems are difficult to recall, even over shorter time periods. 3. Get as much biological material as possible, in spite of the fact that more and more analyses can be done on smaller and smaller amounts of blood, urine, fat tissue, etc. Demand for biological samples is high, and many environmental biomarkers need to be collected within a short time span. Longitudinal biological sampling is important, especially to detect the onset of infections by measuring the circulating antibodies at different time intervals and changes in environmental exposures.
143
4. Keep the principles for sampling and follow-up as simple as possible. Remember that ‘the best is the enemy of the good’. Unless you have unlimited funds and do the study in a work free population there are limits to how many interesting things you can do, and how much time you can expect pregnant women to provide to the study. 5. Make the cohort as large as possible. Forget about sample size calculations and specific hypotheses. Most of the interesting studies will not be envisioned at the time of planning, nor should this be expected. Research ideas evolve over time, as well as research technologies. All experience shows that even large studies are not large enough when you have to identify study subjects exposed to specific environmental or genetic factors. 6. Make sure the database becomes available to other researchers. Only by making an open data source will research opportunities be used best. Experience shows this is not easy, and many people who have spent much time on collecting data feel a strong ownership to the data. An independent steering committee should be established. 7. Pay close attention to research ethics and data confidentiality. With many users of data samples of the cohort data may well be spread on too many hands. Keeping data on central servers and allowing access from outside by using safe log-on procedures is the only way to preserve confidential information. 8. Keep the planning and management group as small as possible. Numerous decisions have to be made, and making the decision process too complicated may jeopardize any reasonable time line for data collection and analyses. 9. Keep data documentation as detailed as possible. Memory is short, and even if data managers and study coordinators remain on the team they also forget, and important decisions may not be known in the future. Keep the documentation easily available and updated, for example at the study website. 10. Provide information about study results to participants. Keeping personal contact with a large number of participants is important, but expensive. The more you can spend on this, the better, but at least make sure research results are available on a public website to the participants in the study. References Arai, J.A., Feig, L.A., 2010. Long-lasting and transgenerational effects of an environmental enrichment on memory formation. Brain Res. Bull. (Epub ahead of print). Barker, D.J., 1990. The fetal and infant origins of adult disease. BMJ 301 (6761), 1111. Barr, C.E., Mednick, S.A., Munk-Jorgensen, P., 1990. Exposure to influenza epidemics during gestation and adult schizophrenia: a 40-year study. Arch. Gen. Psychiatry 47 (9), 869–874. Forsdahl, A., 1978. Living conditions in childhood and subsequent development of risk factors for arteriosclerotic heart diseases. J. Epidemiol. Community Health 32, 34–37. Gluckman, P., Hanson, M. (Eds.), 2006. Developmental Origin of Health and Diseases. Cambridge University Press. Li, J., Olsen, J., Vestergaard, M., Obel, C., 2010a. Attention-deficit/hyperactivity disorder in the offspring following prenatal maternal bereavement: a nationwide follow-up study in Denmark. Eur. Child Adolesc. Psychiatry 19 (10), 747–753. Li, J., Olsen, J., Vestergaard, M., Obel, C., Baker, J.L., Sørensen, T.I., 2010b. Prenatal stress exposure related to maternal bereavement and risk of childhood overweight. PLoS One 5 (7), e11896. Lucas, A., 1991. Programming by early nutrition in man. Rev. Ciba Found. Symp. 156, 38–50. Lucas, A., 1998. Programming by early nutrition: an experimental approach. Rev. J. Nutr. 128 (2 Suppl.), 401S–406S. Lumey, L.H., Stein, A.D., Susser, E., 2010. Prenatal famine and adult health. Annu. Rev. Public Health, Mar 17 (Epub ahead of print). Nahmias, A.J., Nahmias, S.B., Danielsson, D., 2006. The possible role of transplacentally-acquired antibodies to infectious agents, with molecular mimicry to nervous system sialic acid epitopes as causes of neuromental disorders: prevention and vaccine implications. Rev. Clin. Dev. Immunol. 13 (2–4), 167–183. Olsen, J., Melbye, M., Olsen, S.F., Sørensen, T.I., Aaby, P., Andersen, A.M., Taxbøl, D., Hansen, K.D., Juhl, M., Schow, T.B., Sørensen, H.T., Andreasen, J.,
144
J. Olsen / International Journal of Hygiene and Environmental Health 215 (2012) 142–144
Mortensen, E.L., Olesen, A.W., Søndergaard, C., 2001. The Danish National Birth Cohort – it’s background, structure and aim. Scand. J. Public Health 29 (4), 300–307. St Clair, D., Xu, M., Wang, P., Yu, Y., Fang, Y., Zhang, F., Zheng, X., Gu, N., Feng, G., Sham, P., He, L., 2005. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. JAMA 294 (5), 557–562.
Sun, Y., Vestergaard, M., Christensen, J., Nahmias, A.J., Olsen, J., 2008. Prenatal exposure to maternal infections and epilepsy in childhood: a population-based cohort study. Pediatrics 121 (5), e1100–e1107. Virk, J., Li, J., Vestergaard, M., Obel, C., Lu, M., Olsen, J., 2010. Early life disease programming during the preconception and prenatal period: making the link between stressful life events and type-1 diabetes. PLoS One 5 (7), e11523.
Contents lists available at SciVerse ScienceDirect
International Journal of Hygiene and Environmental Health journal homepage: www.elsevier.de/ijheh
Short communication
Nine months that last a lifetime. Experience from the Danish National Birth Cohort and lessons learned Jørn Olsen ∗ Aarhus University, Department of Epidemiology, School of Public Health, Bartholins Allé 2, DK-8000 Aarhus C, Denmark
a r t i c l e
i n f o
Keywords: Pregnancy cohorts Life course epidemiology Fetal programming Follow up attrition Project coordination
a b s t r a c t A growing body of evidence indicates that antenatal care should focus not only on preventing perinatal complications but needs to see the early phase of life as important for a number of adult diseases as well. Most of the research comes from animal studies, since cohorts starting early in life that include biomarkers and have long term follow-up are few, the best known being the National Collaborative Perinatal Project (1959–1974) where only a part of the cohort are being followed (www.birthcohorts.net). Many cohorts are, however, in the planning phase, and the paper provides ten suggestions/recommendations for principal investigators of new or recently established cohorts. © 2011 Elsevier GmbH. All rights reserved.
Introduction Much has been achieved since Forsdahl, Lucas and Barker launched the idea about “fetal programming” or “early origin” of chronic diseases. The role of social conditions, nutrition or fetal growth was key in this phase, suggesting that poor social conditions, impaired fetal growth or lack of proper nutrition early in life might increase the risk of chronic diseases later in life, especially diabetes and cardiovascular diseases (Forsdahl, 1978; Barker, 1990; Gluckman and Hanson, 2006; Lucas, 1991, 1998). Since then many have shown that fetal growth is an important predictor of some chronic diseases that manifest themselves later in life, but the causal implications are still unsettled. Other results indicate that many other exposures early in life, like stress, infections or environmental exposures may have longlasting health effects (Li et al., 2010a, 2010b; Virk et al., 2010), and many disease endpoints are of interest, like mental disorders, cancers, immune diseases and more (Arai and Feig, 2010; Barr et al., 1990; Lumey et al., 2010; Nahmias et al., 2006; St Clair et al., 2005; Sun et al., 2008). There is substantial empirical evidence to support building up an infrastructure for studying the early origin of chronic diseases, especially in the light of the new knowledge about epigenetic modifications of gene expression. We know now that environmental factors may change gene expression through epigenetic mechanisms, and that may modify genetic environmental causes of disease. These epigenetic changes may take place throughout life but are expected to have more impact during fetal life and in early
∗ Tel.: +45 8942 6085; fax: +45 8613 1580. E-mail address: [email protected] 1438-4639/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijheh.2011.10.015
childhood. This new knowledge provides a plausible mechanism for how early exposures may have long-lasting health effects and provides new hopes for disease prevention, even for diseases which were previously believed to be of genetic origin. Furthermore, laboratory facilities and technologies are available for handling large-scale data sources. Gene mapping technologies open up for large-scale screening of millions of gene variants, soon probably full genome sequencing, and the technologies for studying epigenetic changes are getting better and better. What is still lacking are large scale population based cohorts which allow for long-term followup with good attrition. It is important that we set up studies that can identify preventable causes of disease and start as early in life as possible, and they should aim to include (prospective) data from conception to death. In the following, experience from the Danish National Birth Cohort (DNBC) will be presented. The DNBC, a short description The DNBC started recruitment of pregnant women in Denmark in 1996 and by 2002 included data from about 100,000 pregnancies. The objectives of the DNBC were to establish a large scale database with open access that could provide information on modifiable determinants of diseases in childhood and in adult life. The aim is to follow the cohort from conception to death. Details on the project can be found at www.dnbc.dk, but in short: The aim was to recruit pregnant women as early as possible in pregnancy, at best before conception. The best we could do was to recruit women when they came to their first pregnancy visit, which in Denmark is provided by their general practitioner (GP) around gestational week 6–12. At this visit, the GPs who participated in the study (about half of the GPs in the country) provided the
J. Olsen / International Journal of Hygiene and Environmental Health 215 (2012) 142–144
consent form and the background description of the study also called “Better Health for Mother and Child”. At this visit, a blood sample was taken to the study biobank after oral consent. The sample was stored with personal identification if written consent was received by mail. About 60% of the invited women mailed a signed form to the study center. A second blood sample was taken by the GP in the second trimester, and a blood sample from the child (umbilical cord) was taken by midwives shortly after delivery. All blood samples were sent by regular mail to the State Serum Institute in Copenhagen and processed there. This delay in processing blood samples and freezing will be OK for most time stable components in blood but not for other components like certain cytokines, etc. Data on lifestyle factors and environmental exposures were collected by medical questionnaires, computer assisted interviews (CATI) and, more recently, by using web-based questionnaires. We used two mailed questionnaires and 2 CATIs during pregnancy. After the delivery we conducted CATIs at 6 and 18 months, and we used mailed questionnaires or web-based questionnaires in the 7 years follow-up. In the 11 years follow-up, only web-based questionnaires are used at present. We have an ongoing follow-up for all participants based on linkage to existing population based research registers where we e.g. record all inpatient or outpatient contact to all Danish hospitals. We can also include data on redeemed prescribed medicine, changes in social conditions and much more based on linkage to registers established for administrative purposes. Endpoints in this study will therefore come from routine diagnosing in hospitals as reported to the national hospital register or some of the clinical databases, use of prescribed drugs or ad hoc data recorded at one of the follow up points (at present, 6 months, 18 months, 7 years and 11 years postpartum). Although response rates to data collection rounds that involve participants’ active collaboration are 50–70%, very few use their option to leave the study. Most participants accept to be invited for new data collection rounds. More information on the DNBC is available in our descriptive papers (Olsen et al., 2001) or on the website that also provides a reference to all publications based on the cohort data (www.dnbc.dk).
Lessons learned and 10 recommendations for further pregnancy cohort planners 1. Plan for long-term follow-up and make sure to have a budget to cover basic maintenance and running costs; contact to participants, data documentation, data cleaning and follow-up of participants. Like biologists, physicists and others need laboratories and machines, epidemiologists need data, and cohorts are part of our infrastructure. Do not underestimate these running costs. 2. Start data collection as early as possible. The time period of organogenesis is mainly over after 3 months of gestation. Make such as much data as possible is collected prospectively, before the occurrence of the endpoint of interest. Focus on data that cannot be recalled back in time; especially data on diet, medicine intake and short-term health problems are difficult to recall, even over shorter time periods. 3. Get as much biological material as possible, in spite of the fact that more and more analyses can be done on smaller and smaller amounts of blood, urine, fat tissue, etc. Demand for biological samples is high, and many environmental biomarkers need to be collected within a short time span. Longitudinal biological sampling is important, especially to detect the onset of infections by measuring the circulating antibodies at different time intervals and changes in environmental exposures.
143
4. Keep the principles for sampling and follow-up as simple as possible. Remember that ‘the best is the enemy of the good’. Unless you have unlimited funds and do the study in a work free population there are limits to how many interesting things you can do, and how much time you can expect pregnant women to provide to the study. 5. Make the cohort as large as possible. Forget about sample size calculations and specific hypotheses. Most of the interesting studies will not be envisioned at the time of planning, nor should this be expected. Research ideas evolve over time, as well as research technologies. All experience shows that even large studies are not large enough when you have to identify study subjects exposed to specific environmental or genetic factors. 6. Make sure the database becomes available to other researchers. Only by making an open data source will research opportunities be used best. Experience shows this is not easy, and many people who have spent much time on collecting data feel a strong ownership to the data. An independent steering committee should be established. 7. Pay close attention to research ethics and data confidentiality. With many users of data samples of the cohort data may well be spread on too many hands. Keeping data on central servers and allowing access from outside by using safe log-on procedures is the only way to preserve confidential information. 8. Keep the planning and management group as small as possible. Numerous decisions have to be made, and making the decision process too complicated may jeopardize any reasonable time line for data collection and analyses. 9. Keep data documentation as detailed as possible. Memory is short, and even if data managers and study coordinators remain on the team they also forget, and important decisions may not be known in the future. Keep the documentation easily available and updated, for example at the study website. 10. Provide information about study results to participants. Keeping personal contact with a large number of participants is important, but expensive. The more you can spend on this, the better, but at least make sure research results are available on a public website to the participants in the study. References Arai, J.A., Feig, L.A., 2010. Long-lasting and transgenerational effects of an environmental enrichment on memory formation. Brain Res. Bull. (Epub ahead of print). Barker, D.J., 1990. The fetal and infant origins of adult disease. BMJ 301 (6761), 1111. Barr, C.E., Mednick, S.A., Munk-Jorgensen, P., 1990. Exposure to influenza epidemics during gestation and adult schizophrenia: a 40-year study. Arch. Gen. Psychiatry 47 (9), 869–874. Forsdahl, A., 1978. Living conditions in childhood and subsequent development of risk factors for arteriosclerotic heart diseases. J. Epidemiol. Community Health 32, 34–37. Gluckman, P., Hanson, M. (Eds.), 2006. Developmental Origin of Health and Diseases. Cambridge University Press. Li, J., Olsen, J., Vestergaard, M., Obel, C., 2010a. Attention-deficit/hyperactivity disorder in the offspring following prenatal maternal bereavement: a nationwide follow-up study in Denmark. Eur. Child Adolesc. Psychiatry 19 (10), 747–753. Li, J., Olsen, J., Vestergaard, M., Obel, C., Baker, J.L., Sørensen, T.I., 2010b. Prenatal stress exposure related to maternal bereavement and risk of childhood overweight. PLoS One 5 (7), e11896. Lucas, A., 1991. Programming by early nutrition in man. Rev. Ciba Found. Symp. 156, 38–50. Lucas, A., 1998. Programming by early nutrition: an experimental approach. Rev. J. Nutr. 128 (2 Suppl.), 401S–406S. Lumey, L.H., Stein, A.D., Susser, E., 2010. Prenatal famine and adult health. Annu. Rev. Public Health, Mar 17 (Epub ahead of print). Nahmias, A.J., Nahmias, S.B., Danielsson, D., 2006. The possible role of transplacentally-acquired antibodies to infectious agents, with molecular mimicry to nervous system sialic acid epitopes as causes of neuromental disorders: prevention and vaccine implications. Rev. Clin. Dev. Immunol. 13 (2–4), 167–183. Olsen, J., Melbye, M., Olsen, S.F., Sørensen, T.I., Aaby, P., Andersen, A.M., Taxbøl, D., Hansen, K.D., Juhl, M., Schow, T.B., Sørensen, H.T., Andreasen, J.,
144
J. Olsen / International Journal of Hygiene and Environmental Health 215 (2012) 142–144
Mortensen, E.L., Olesen, A.W., Søndergaard, C., 2001. The Danish National Birth Cohort – it’s background, structure and aim. Scand. J. Public Health 29 (4), 300–307. St Clair, D., Xu, M., Wang, P., Yu, Y., Fang, Y., Zhang, F., Zheng, X., Gu, N., Feng, G., Sham, P., He, L., 2005. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. JAMA 294 (5), 557–562.
Sun, Y., Vestergaard, M., Christensen, J., Nahmias, A.J., Olsen, J., 2008. Prenatal exposure to maternal infections and epilepsy in childhood: a population-based cohort study. Pediatrics 121 (5), e1100–e1107. Virk, J., Li, J., Vestergaard, M., Obel, C., Lu, M., Olsen, J., 2010. Early life disease programming during the preconception and prenatal period: making the link between stressful life events and type-1 diabetes. PLoS One 5 (7), e11523.