The flowchart of this scoping review (Fig. 1) describes the results of screening and research selection processes. We found 2,752 records by database searching. After removing 1,399 duplicated records, 1,353 articles were eligible for the initial screening of titles and abstracts. Among these, 59 articles were determined to be qualified for full-text reviews. Ultimately, 11 multigenerational cohort studies were identified through electronic search. A further 17 eligible cohort studies were identified by a manual search of reference lists and cohort databases. Therefore, this scoping review identified 28 unique multigenerational cohort studies in total. The study characteristics of included multigenerational cohort studies are detailed in Appendix 2.
Study design
Based on this scoping review and previous literature 23, 24, we classified the included multigenerational cohort studies into four categories (Fig. 2). In general, a population-based cohort extended three generation cohort was initiated as a population-based cohort with collected information from original participants (F0). As the cohort grew, the offspring of the original participants were recruited as F1 (F0’s children) and extended to F2 (F0’s grandchildren). Secondly, the birth cohort extended three generation cohort was initiated as a birth cohort with collected information on pregnancies (F0) and their fetus (F1). As the cohort extended, F1's children were recruited as F2. While the three generation cohort was initiated with a three-generation study design at the very beginning stage, having a data collection strategy to collect information on F0 (grandparents), F1 (parents) and F2 (grandchildren) at the same stage. Finally, the integrated birth and three generation cohort was initiated as a birth cohort with collected information on pregnancies (F1) and their fetus (F2) while integrating a three-generation study design with F0 (F1’s parents) information collected plan. As shown in Fig. 3, among the included 28 multigenerational cohort studies, most cohorts (n = 15, 53%) were categorized as birth cohort extended three generation cohort. Nine population-based cohorts extended three generation cohorts (32%) and three three generation cohorts (11%) in total. In comparison, only one study (4%) was identified as integrated birth and three generation cohort.
Geography
The 28 multigenerational cohorts were conducted in 19 countries worldwide (Fig. 4). The majority of the cohorts (n = 6, 21%) were conducted in the United States, followed by the United Kingdom (n = 3, 11%), Australia (n = 3, 11%), Germany (n = 3, 11%), and Netherlands (n = 2, 6%). The rest cohorts (n = 10, 37%) were from France, Japan, Sweden, Ireland, Brazil, Canada, Denmark, New Zealand, Filipino, and Israel, respectively. And one cohort (3%) conducted fieldwork in Northern Europe (Norway, Denmark, Sweden, Iceland, and Estonia), Spain, and Australia. We can see that most cohorts were conducted in Europe (n = 12, 43%) and North America (n = 7, 25%). There were fewer included cohorts from Oceania (n = 4, 15%) and Asia (n = 3, 12%). And only one study came from South America (4%). According to World Bank classification by income, most cohorts (n = 26, 93%) came from high-income countries. The remaining two cohorts were from middle-income countries (7%).
Time range and follow-up of F2
The study duration and follow-up of F2 differed by cohort. Each cohort adhered to its unique protocol, depending on its purposes, hypotheses and available funding. Figure 5 demonstrates the included cohorts’ time range and cumulative years of follow-up of F2. The study duration of F2 ranged from two years (MUSP cohort) to 31 years (NCDS cohort). The earliest year of F2’s data collection was 1990 (PAS cohort); the most recent was 2016 (93Cohort-II and MUSP cohort). There were 11 cohorts (39%) that started the data collection of F2 between 2000 and 2010, and nine cohorts (32%) started after 2010. As for follow-up of F2, the shortest cumulative years of follow-up of F2 was six months from the MUSP cohort, while the longest follow-up of F2 was 20 years from the Nova Scotia 3G cohort. And the number of follow-up waves of F2 also varied across included cohorts. Most cohorts conducted less than five waves of data collection of F2 until now. While the Nova Scotia 3G cohort conducted over 20 waves of data collection of F2. Most of the cohorts still had ongoing data collection and follow-up.
Sample size
The sample size of included cohorts varied largely from 41 to 167,729. Except for the Illawarra Born Cohort (4%) included only 41 participants, most of (n = 15, 53%) the included cohorts' sample size was between 1,000 and 10,000, and the rest (n = 12, 43%) cohorts' sample size was over 10,000. There are two cohorts' sample sizes beyond 100,000: the Lifelines cohort (167,729) and the UBCoS Multigen cohort (140,000).
Participants
Although several cohorts were initiated very early and comprised up to five-generation participants, due to the loss of follow-up and a large variety of missing data from the previous generations, except for the Lifelines cohort included integrated four-generation participants' information, the other 27 cohorts' participants had three-generation information. Most cohorts’ participants were enrolled from one city of a country, such as Miyagi Prefecture in Japan, Uppsala in Sweden, and Framingham in the United States. However, the Lifelines cohort conducted their survey in the northern three provinces of the Netherlands, the NCDS cohort's participants came from England, Scotland and Wales, and the RHINESSA cohort recruited participants from seven countries. Almost all studies sought to enroll individuals in the general population, excluded the NCI-DES cohort’s inclusion criteria were diethylstilbestrol exposed and unexposed mothers and their offspring, and the DFBC cohort recruited people who went through the Dutch famine and their offspring.
Data collection
Data collection of each cohort was summarized in Table 1. We classified the data into six categories following relevant references 24–26: physical examination, general information, health status, lifestyle and environment, psychosocial parameters, and biomaterials and genomics. Usually, the data collected in F0 was consistently collected in both F1 and F2. Such as general information, health status, lifestyle and environment have been collected continuously through three generations for all cohorts. But some cohorts modified their data collection strategy at F2 with either added or deleted aspects. For example, NLSY79 cohort and Illawarra Born cohort deleted psychosocial parameters; Add Health cohort deleted psychosocial parameters and biomaterials and genomics; PSID-CDS cohort added psychosocial parameters; IOW 3rd Gen cohort, Dunedin cohort, MUSP cohort, and 93Cohort-II cohort added biomaterials and genomics; JPS-FUS cohort added psychosocial parameters and biomaterials and genomics in F2 data collection.
Table 1
Summary of data collected by three generations of included multigenerational cohort studies a
Study | F0 b | F1 b | F2 b |
| PE | GI | HS | L&E | PP | B&G | PE | GI | HS | L&E | PP | B&G | PE | GI | HS | L&E | PP | B&G |
FHS-Gen3 | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
RHINESSA Cohort | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ |
DCH-NG Cohort | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
ATPGen3 | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
CLHNS | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ |
NCI-DES | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ |
NLSY79 | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ | √ | √ | √ | | |
PSID-CDS | | √ | √ | √ | | | | √ | √ | √ | | | | √ | √ | √ | √ | |
E4N | √ | √ | √ | √ | | | √ | √ | √ | √ | | | √ | √ | √ | √ | | |
IOW 3rd Gen | √ | √ | √ | √ | | | √ | √ | √ | √ | | | √ | √ | √ | √ | | √ |
UBCoS Multigen | | √ | √ | √ | √ | | | √ | √ | √ | √ | | | √ | √ | √ | √ | |
ALSPAC-G2 | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
93Cohort-II | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | √ |
Nova Scotia 3G | √ | √ | √ | √ | | | √ | √ | √ | √ | | | √ | √ | √ | √ | | |
Dunedin Cohort | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | √ |
NCDS | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
DFBC | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
Add Health | | √ | √ | √ | √ | | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | | |
Illawarra Born | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | | √ |
JPS-FUS | √ | √ | √ | √ | | | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
MUSP | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
ACROSSOLAR Study | √ | √ | √ | √ | | | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ |
GINIplus Birth Cohort | | √ | | | | | √ | √ | √ | √ | | | √ | √ | √ | √ | | √ |
LISAplus Birth Cohort | | √ | | | | | √ | √ | √ | √ | | | √ | √ | √ | √ | | √ |
LifeLines Cohort | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
Lifeways Cohort | √ | √ | √ | √ | | | √ | √ | √ | √ | | | √ | √ | √ | √ | | |
PAS | √ | √ | √ | √ | √ | | √ | √ | √ | √ | √ | | √ | √ | √ | √ | | |
TMM BirThree Cohort | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ | √ |
a: Explanation of the collected data’s category |
• Physical Examination (PE): Anthropometry, blood pressure, pulmonary function, electrocardiogram, skin autofluorescence, neuropsychiatric health, cognition, etc. |
• General Information (GI): Demographics, socioeconomics, family composition, employment, education, income, etc. |
• Health Status (HS): Medical history, medication use, healthcare use, reproductive health, child birth and development, birthweight, etc. |
• Lifestyle and Environment (L&E): Physical activity, nutrition, diet, smoking, alcohol using, drug taking, sleep, physical environment, etc. |
• Psychosocial Parameters (PP): Depression, anxiety, quality of life, well-being, health perception, somatization, personality, stress, social support, independence, etc. |
• Biomaterials and Genomics (B&G): Blood sample, urine sample, DNA etc. |
b: F0: Generation 1/grandparents; F1: Generation 2/parents; F2: Generation 3/children. |
Exposures
Across included multigenerational cohort studies, a large number of exposures and outcomes were adopted. Compared to traditional cohorts, the multigenerational cohort studies especially focus on F0 and/or F1 exposures and the corresponding F2 health outcomes. The main exposures of included multigenerational cohort studies are shown in Fig. 6. The size of each rectangle in this tree map is proportional to the number of exposures from all included cohorts. Almost all cohorts had common exposures related to general information (demographics and socioeconomics such as age, education, employment, marital status, and income) and lifestyle and environment (cigarette and alcohol consumption, drug taking, physical activity, dietary and nutrition, physical environment). Also, many cohorts used collected health status information of F0 and/or F1 over the life course as exposures. Furthermore, psychosocial parameters (parental involvement, stressful life events, marital conflict, and periods of lone parenthood) and biomaterials and genomics (sex, race, genetics) were frequently treated as exposures as well. Notably, among these collected data, reproductive factors (hormones, menopause, contraception, marital and fertility histories, mode of feeding) and childhood factors were often taken as exposures in some cohorts. In addition, a few cohorts investigated the natural events’ influence on three generations, such as the TMM BirThree cohort used earthquake and tsunami disasters, the ALSPAC-G2 cohort used major changes that have occurred over the last 20–25 years, and the Dutch Famine Birth Cohort Study used famine as exposures.
Outcomes
Figure 7 displays the main outcomes of included multigenerational cohort studies. The size of each rectangle in this tree map is proportional to the number of outcomes from all included cohorts. The multigenerational cohort studies usually took intergenerational inheritance of diseases as the outcome. The most frequently investigated diseases were obesity, cardiovascular diseases (stroke, heart failure, angina pectoris, myocardial infarction, coronary heart disease, and atrial fibrillation), and child health (low birthweight of infancies, child physical and/or mental development). Followed by mental health (depression, anxiety, autism, post-traumatic stress disorder, suicide), respiratory health (asthma, chronic obstructive pulmonary disease), diabetes mellitus, and hypertension. Besides, cancers (breast cancer, ovarian cancer, prostate cancer, endometrial cancer), cognition function (dementia), reproductive health (pre-eclampsia, gestational hypertension, endometriosis), allergic disease (atopic dermatitis, eczema, rhinitis, food allergy) and social inequality were also taken as outcomes by some cohorts. Few studies also investigated more specific diseases, such as headaches and oral health.
Topics
Overall, most of the included multigenerational cohort studies are population-based and have collected vast amounts of data on many domains which generally covered the exposures and outcomes of those cohorts. They explored the environmental, socioeconomic, lifestyle, physiological, metabolic, genomic and/or epigenomic contributions to health across the life course and generations and boosted verification of the DOHaD hypothesis. Still, some studies have a particular focus, such as cardiovascular diseases (FHS-Gen3 cohort), lung health (RHINESSA cohort), diethylstilbestrol (NCI-DES cohort), famine (DFBC cohort), and cardiometabolic risk (JPS-FUS cohort). Specially, the UBCoS Multigen cohort, 93Cohort-II cohort and MUSP cohort took health inequalities as one of their topics. Despite their various topics and focus, most studies aim to investigate the disentanglement of genetic, lifestyle, and environmental influences on disease development and to study the between-generation similarities.