Iva Šunić^1*, Natalija Novokmet¹, Jelena Šarac¹, Dubravka Havaš Auguštin¹, Nives Fuchs¹ & Rafaela Mrdjen – Hodžić¹

¹Institute for Anthropological Research, Zagreb, Croatia

* Corresponding author: iva.sunic@redesign.inantro.hr

https://doi.org/10.54062/jb.1.1.7

Keywords: Cohorts, Pregnancy, Newborns, Epidemiology, Europe

Introduction

Recently, it has become increasingly apparent that new and modern lifestyles have considerably greater adverse and long-term health effects that it has been perceived previously. Health issues such as metabolic diseases, mental health, and respiratory system diseases and alike, which in most cases are preventable, are becoming more common due to the sedentary lifestyle, unhealthy dietary patterns, polluted environment and everyday stress. Although many studies investigate the causes and consequences of these problems, in recent decades the prevailing research models have become cohorts. Such studies have a sample that represents a specific segment of the population (share the same characteristics such as age, gender, place of residence etc.) as a study subject and they can be prospective and retrospective. Prospective studies look for outcomes of certain exposures, whereas retrospective studies look backwards comparing two groups of people, one under a certain exposure and the other unexposed. Birth cohort studies are especially suitable study methods for understanding the influence of the environment in which a child develops during pregnancy, on its development later in life and its overall health. The main advantage is that there are no limits to follow-ups and health outcomes can be monitored until adulthood or even further in life (Brandstetter et al., 2019). In addition, because of the large difference between children in different regions, even within the same country, a general approach is an excellent tool for comprehensive research. Possible adverse outcomes of pregnancy are very important to identify early on in order to prevent them in the future or in other risk groups. In that way, many public health issues can be monitored and prevented. Most of European populations have a problem with low birth rates and an ageing population and it is becoming an increasing burden for the social and health systems. Childhood is the best period for action because it is the most effective time to promote good health and healthy life choices, which can then also be passed on to next generations (Golding, 2006; Larsen et al., 2013).

The number of cohort studies in Europe has been growing in the last 80 years. Generally, they start in the prenatal period and end after birth with one or several follow-ups of children. Although extremely useful, this research model is time and money consuming. Therefore, collaboration and data sharing between study groups is expected. The aim of this paper is to list all cohort studies of pregnancy and birth that have taken place in Europe, as well as to offer a general overview. Data shared between cohorts can reduce time and resources needed for the studies. The strength in drawing conclusions and causal effects on a larger number of participants is also one of the advantages of collaboration and data sharing. Not only that, the challenges and obstacles in individual research can provide useful information for improving future research models. (Larsen et al., 2013).

Materials and methods

Pregnancy and birth cohorts’ data was collected from multiple sources.  Online databases such as PubMed and Google Scholar were inspected, as well as Google with keywords ‘birth cohort’, ‘pregnancy cohort’, ‘newborns’, ‘pregnancies’, ‘childhood asthma’, ‘childhood obesity’, ‘illness in early childhood’, ‘epidemiological study of newborns’. Pages https://www.birthcohorts.net/, http://chicosproject.eu/ and https://lifecycle-project.eu/ were reviewed. Birthcohorts.net is a database that collects information about birth cohorts worldwide. It was established to enable easier access to data and study designs and to promote collaboration between distinct study groups. Cohorts in this database have at least one year of follow-up, have been established before/during pregnancy or at birth and have at least 300 mother-child pairs (Birthcohorts, 2021). ‘CHICOS: Developing a Child Cohort Research Strategy for Europe’ is a project funded by the European Union’s 7th Framework Programme for Research and Technological Development. The aim of CHICOS is to improve child health by evaluating existing data about mother-child cohorts, determining gaps in research and focusing on future studies (CHICOS project, 2021). The ‘EU Child Cohort Network: A Europe-wide network of cohort studies started in early life’ has been developed to bring together cohort studies in Europe. Its overall aim is to determine the effect of early-life environment and possible stressors on developing health problems later in life (LifeCycle, 2021). Each of the mentioned databases and articles is created according to certain own criteria. This review brings together data from databases and articles, with the intent of harmonizing and making data more accessible.

Inclusion criteria for cohorts were that the study population was based in Europe and that the subjects of studies were pregnant women and subsequently their children, or that newborns were included in the study. There was no time or size limit on found cohorts. Therefore, only studies that have an extended period of observation and continuity were taken into consideration due to the fact that it was sometimes hard to separate what is a continuous study and what is a one-time study of one cohort. Europe as inclusion criteria imply countries that are part of the continent using defined natural borders.

The majority of data and information on subjects was found on the Birthcohorts website, where the researchers submit information themselves. For other studies, official websites of research groups and their published articles were reviewed. Data collected from websites and articles comprise the name of the cohort, its country of origin, main aim, number of subjects in the cohort, other family members included in the study and duration of the follow-up period with parents and child.

Results and discussion

As expected, the most developed European countries have the largest and most extensive studies.  Of all the cohorts, more than half (n = 113) are in the countries of Northwest and Central Europe. Italy, Germany and the United Kingdom have the greatest number of cohorts and the most diverse studies (Figure 1.).

Figure 1.: Number of cohorts per country

127 studies consisting of 137 cohorts spread out in 27 countries were found (Table 1).

Table 1 Pregnancy and birth cohorts in Europe and their characteristics. All data are participants on the baseline. Source: website birtcohorts.eu and stated references.

29 cohorts are a part of bigger consortium, where cohort studies are being conducted simultaneously in several partner countries (AMICS, ELSPAC, EuroPrevall study, CHOPIN, PHIME, SPACE studies). CHOPIN has cohorts in Belgium, Germany, Italy, Poland and Spain and is concentrated on early life nutrition and its possible influence on obesity later in life (Koletzko et al., 2009). PHIME focuses on early life nutrition but aims to investigate the level of heavy metals in blood and breast milk accumulated through the nutrition. Cohorts are in Croatia, Greece, Italy and Slovenia (Miklavčič et al., 2013). Both SPACE and AMICS are focused on the development of asthma and atopy in childhood. AMICS has two cohorts in Spain, and one in Germany and the United Kingdom (Fríguls et al., 2009; Iliadou et al., 2019). The EuroPrevall study is also investigating allergy but from a nutritional aspect. In addition, data related to the cost of food allergies and quality of life was also obtained. The study was conducted in the following countries: Germany, Greece, Iceland, Italy, Lithuania, the Netherlands, Poland, Spain and the United Kingdom. To improve epidemiological knowledge of factors influencing children’s health in European countries, WHO started ELSPAC. ELSPAC consists of four studies: ALSPAC in the UK, FCOU in Ukraine, one on the Island of Man and one in the Czech Republic. Other cohorts collected data in Slovakia and the Russian Federation but encountered political and financial problems, while Greece and Estonia stopped collecting data because of the lack of funds (WHO, 1997, 1998, 1999).

The most common method of collecting data is via questionnaires. Interviews and educational assessments are used later in the child’s life. Information includes the socio-demographic status of parents, their lifestyle and environmental exposures, as well as mother’s pregnancy characteristics, depending on the main aim of the study. Most common participants are mother-child pairs. Half of them included fathers as well, but only a few included siblings, grandparents or other family members. Their inclusion is often associated with the main goal of a study, for example in allergies and atopic diseases research, family medical history and current living conditions are useful information for the evaluation of infants’ health.

Most of the cohorts have specific enrolment criteria, such as mothers over 18 years of age that are native language speakers (for the comprehension of study procedures), healthy mothers without a history of chronic diseases, singleton pregnancy etc. If a study has a specific aim, the inclusion and exclusion criteria are formed accordingly. Examples include MUBICOS in Italy, a cohort study that researches only twins so their inclusion criteria are only twin pregnancies (Brescianini et al., 2013, 2016). When investigating allergies, cohorts like SPACE have their own inclusion criteria such as the parent’s medical history of respiratory diseases or parental IgE results or for children, a manifestation of atopic diseases (Tsitoura et al., 2002). The most common criteria are still healthy mothers living in a specific area in which the study is taking place. For most of the studies, the enrolment period begins at pregnancy and follow-up continues at least a couple of years after birth (Figure 2.).

Figure 2.: Follow-up period children

Enrolment usually starts with the pregnancy or after the birth of a child (Figure 3.).

Figure 3.: Follow up period parents

Only a few studies differ, including the Southampton Women’s Survey. In the survey, the parental data is collected before the pregnancy so that their associations to perinatal and infant outcomes can be evaluated (Inskip et al., 2006). In addition, the UppSTART study from Sweden recruits couples undergoing assisted reproductive techniques to determine if parental lifestyle has an influence on conception, pregnancy or assisted reproduction procedure-specific outcomes. UppSTART also investigates possible epigenetic alterations in infants conceived via assisted reproductive techniques, compared with infants conceived spontaneously (Iliadou et al., 2019). The Swedish BASIC study follows women’s experiences during and after pregnancy. in order to offer timely and appropriate help to women who feel unwell. Biosamples from both mother and child are also collected for further analyses (BASIC, 2021).

Factors that have an influence on general health and the wellbeing of mother-infant pairs are cited as the main goal in almost half of the studies (n=61) (Figure 4.).

Figure 4.: Scientific area of research

The objective is generally to describe and understand how lifestyles, environment, education and other socio-economic factors affect the course of pregnancy and childbirth. The child’s development and growth are examined later on. The respiratory system and its development, diseases and risk factors for their occurrence are among the most researched subjects. It has been noted that several factors have an impact on the development of childhood asthma. Besides genetic factors, environmental influence also has an important role in the etiology of a disease, the most prominent one being socio-economic status and housing. Blood samples, which are used for detecting the level of IgE, family history of atopic diseases, number of siblings or people in the household, parental education and indoor pollution (types of heating, pets, mold etc.), are correlated to the allergies of young children (Bisgaard, 2004; de Korte-de Boer et al., 2015; Martindale et al., 2005). Most of the cohorts that investigate atopic diseases and allergies have the same pattern regarding cohort size due to the fact that children with a family history of atopic diseases have a larger risk for developing the same. It is for this reason that cohorts usually include other family members such as the Russian Moscow newborns 2011 eczema study. This cohort included both parents, grandparents, siblings and all first relatives. Data collected includes allergy manifestation to determine if there is gender or some other pattern of incidence of atopic diseases in newborns whose family has a history of such diseases (Treneva et al., 2015). Another major health concern is obesity whose percentage in the population is growing each year. That is why metabolic diseases, such as diabetes and metabolic syndrome, as well as nutrition and gut microbiome are very often part of a cohort’s research. Many studies investigate different aspects of nutrition and diet-related issues. HELMI study focuses on factors that modify intestinal microbiome in infants and its relation to its health and well-being. This subject is becoming increasingly popular as there is more and more evidence of gut microbiome having potential long-term consequences on health in individuals (HELMi, 2019). CRIBS is focused on biological, environmental and behavioral risk factors for metabolic syndrome and study results serve as a base for the development of intervention strategies (Havaš Auguštin et al., 2020; Zajc Petranović et al., 2018). In addition to nutrition and allergies, studies concerning exposure to chemicals, pollutants and tobacco smoke have been investigated with a similar frequency. Environmental pollutants can have an immense impact on children’s health, especially on development during the gestation period. Chemicals such as organochlorines, polycyclic aromatic hydrocarbons (PAHs), dioxins and heavy metals have an adverse effect on neurological development and the immune system. These pollutants are known to accumulate in marine food chains and are closely monitored in populations where the diet is based on seafood, namely the Mediterranean countries and the Faroe Islands. Both PHIME and CHEF research long-term, low-level environmental exposure to toxic and essential metals via food. CHEF also focuses on the health of children and adults with an emphasis on the impact of a seafood diet and on marine contaminants (Miklavčič et al., 2013). Particulate matter (PM) is measured as an air pollutant since it covers all liquid and solid particles suspended in the air. Dust, pollen, smoke, soot and liquid drops are all considered PM and are highly concentrated in industrial areas and heavy traffic areas. The Portuguese GISA study is a retrospective cohort study, which tries to assess the relationship between air pollution and low birth weight and preterm birth outcomes. Similarly, in the Czech Republic, PM in air was measured in a highly industrial region and its impact on the retardation of fetal growth was examined. Results were compared to those of a mountain region, without pollution (Dejmek et al., 2000). Problems concerning mental health and neurological development have also been analyzed and several studies focus only on this topic. CCCC 2000 investigates mental health problems and associated factors in infancy and their association with psychopathology in later childhood, as well as possibilities of intervention from infancy onwards (Skovgaard et al., 2005). FinnBrain investigates the effects of prenatal and early life stress exposure on child health and brain development. It has primarily neurodevelopmental focus and aims at identifying biomarkers related to early life and prenatal stress exposures as well as trajectories for common psychiatric and somatic illnesses such as depression, anxiety and cardiovascular illnesses (Karlsson et al., 2018). Very often all of the above-mentioned problems are interconnected, for instance many studies that investigate atopic diseases consider environmental pollution or nutrition as factors that could cause problems with the respiratory system. The GINI study investigates whether the development of allergic diseases can be influenced by early childhood nutrition (von Berg et al., 2003). Breastfeeding and dietary habits, including organic food and a vegetarian diet, are also mentioned in the KOALA birth cohort study which tries to identify factors that influence the clinical expression of atopic disease (Kummeling et al., 2005). The Swedish ALADDIN study also has a unique view on the allergy development in childhood. The population in this study practices anthroposophical lifestyle which is characterized by organic diet, home deliveries, restricted use of medicines and alike (Stenius et al., 2011). Besides metabolic syndrome, the CRIBS study also focused on psychological health and quality of life of pregnant women (Delale et al., 2021), while the Kraków Cohort tries to connect all three key problems, nutrition during pregnancy, exposure to environmental pollutants and the manifestation of eczema in children (Jedrychowski et al., 2003).

In addition to regular cohort studies, fertility studies, biobanks, and prevention programs were also included in this review. Each collects a sizable amount of data, but only several cover a broader variety of research subjects. BabyCare in Germany is a program to prevent preterm birth with an extensive database which is used for follow-up surveys (Kirschner & Friese, 2012). Nascere in Friuli Venezia Giulia is not an official cohort study, but data routinely collected by the Regional Health Authority and is used for studies such as asthma, allergies, diet during pregnancy and mercury levels (Pitter et al., 2016). Some birth cohorts are a part of bigger cohort groups who include people of different age. Lifelines in the Netherlands is a large, multigenerational cohort study that has been on-going for 30 years, over three different generations and has over 167,000 participants (Lifelines, 2021). Likewise, Swedish LifeGene is both a cohort study and a database consisting of whole families of different age groups. The project offers an opportunity to involve couples prior to and during pregnancy, meaning children that are going to be born into the cohort are going to have complete pre- and perinatal data from both the mother and father (Almqvist et al., 2011).

Although pregnancy and birth cohorts are usually established to detect future outcomes, there are few that use older data and records for retrospective research. The Helsinki Birth Cohort Study includes people who were born 80 years ago. Old medical records are used to compare childhood data to health outcomes in old age such as coronary diseases, cancer and mental health (Maelstrom Research, 2021). The Newcastle 1000 Families started as a study of health in newborns, continuing over a few decades and now researches the health of its original newborns in their 70s. Similarly, PLASTICITY follows the lives of children born from 1971 to 1974 and aims to explore how the neonatal risk factors modulate neurodevelopmental and neurodegenerative processes such as learning disabilities, ADHD, ageing, the early onset mild cognitive impairment, dementia and like. It is believed that perinatal adverse events have an unexpectedly deleterious effect on the brain at a middle and older age (Hokkanen et al., 2013). These cohort studies are excellent for determining long-term consequences on health, but its problem is tracking down all of the participants after such a lengthy period (Thousand Families, 2009).

Most common restrictions and limitations in cohort studies are time-consuming methods and results which depend on the honesty of the participants and their willingness to respond to follow-ups. The number of children decreases with each follow-up in every cohort, which can alter results and make comparisons difficult. In addition, collecting biosamples is a challenging and demanding process, which must be specifically coordinated and conducted according to strict ethical guidelines. Nonetheless, study design of the birth cohort studies is suitable for estimating an association between risk factors during prenatal period and the possible health problems in newborns, potentially up to adulthood. New insights from these studies can be implemented in health interventions or used in specific medical cases. The biggest advantage is the wide range of information collected such as psychosocial, genetic and epigenetic, as well as exposure data. Problems arising from having such multitude of information is harmonizing data over multiple studies because each have their own methods. On the other hand, having a variety of methods can be advantageous in estimating which one is most suitable for different field of interest. There is also a discrepancy in number and multitude of cohorts between progressive countries from Northwest and rest of the Europe. While some of the countries are just beginning their research, the UK, Denmark and Germany, to name a few, have been doing researches for many years, some even decades. In such cases, collaboration and shared knowledge are useful to avoid problems that others have already encountered and to establish a good study design that will provide solid data that can be shared later without harmonization problems.

Conclusion

The main aim of this paper is to review and summarize all cohort studies that have been carried out or are still being conducted in Europe. More than 137 cohorts have been found in 27 countries. Exact number of studies is 127 due to the number of them had been or are being conducted internationally, meaning that they collect information from multiple cohorts in different European countries. General concern is well being of mother and child pairs. Numerous cohorts are trying to resolve common health problems in childhood, main being respiratory diseases. Occurrence of allergy in infants has been connected to family history of atopic diseases, number of siblings or people in the household, parental education and indoor pollution. New problem arising in recent years is obesity. Many cohorts are researching connections of pre and postnatal exposures that may have influence on obesity later in life. Mother’s BMI and eating habits during pregnancy, smoking and socioeconomic status are implied to have an impact on child’s weight later in life. Another problem that has arisen with modern lifestyle is pollution. Connection between PM and retardation of fetal growth have been made. Chemical pollution also has great impact on health, showing that they can alter neural development. Many studies have combined all of these problems and are trying to find connection between obesity, childhood respiratory problems and environmental pollution from the early age. It is known that obesity is a risk factor for asthma and that obese asthmatics have more severe symptoms, as well as polluted environment, indoors and outdoors, having impact on respiratory system and general health. However, early indications for these connections are still not well understood and therefore relevant research subject. Such problems are an excellent example of the benefits of cohort study design and collaboration among research groups. Birth cohorts are an important source of information, excellent for comparing regional differences between cohorts, discovering impacts on people’s health and causes of diseases. Collaboration between different birth cohorts is crucial for further harmonization of collected data and their use in the public health systems worldwide for prevention and education.

Acknowledgements

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

The authors have no conflicts of interest to declare.

This research received no specific grant from any funding agency, commercial entity or not-for-profit organization. The CRIBS study which prompted this review paper was funded by a grant of the Croatian Scientific Foundation (HRZZ UIP-2014-09-6598).

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Received: October 7^th, 2021;

Accepted: December 13^th, 2021 ;

Online first: December 16^th, 2021;

Published: TBA

Copyright: © 2021 Šunić et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.