Health consequences of adverse fetal growth : studies in twins

Findings of associations between birth weight and adult health outcomes have been taken to indicate that fetal growth – and fetal nutrition in particular – may program future health and disease in the developing individual. However, the study of prenatal exposures in humans is challenging, and most of the evidence to support fetal programming thus rests on proxy measures, such as birth weight and birth weight for gestational age. These measures are not only crude indicators for fetal growth and fetal nutrition, but also influenced by many other factors, some of which may be involved in disease development (common causes).

The aim of this thesis has been to make use of the unique features of twins to increase the understanding of potential health consequences of adverse fetal growth. Birth weight differences within twin pairs target a specific measure of fetal growth, and within-twinpair comparison further allows for evaluation of the influence of fetal growth independent of factors shared by the twins in a twin pair. Some of these factors (e.g. early socioeconomic environment and genetic factors) have been proposed to potentially confound associations between birth weight and adult disease. Twins as a group are further exposed to a more adverse fetal environment than singletons. By comparing adult morbidity and mortality in twins to singletons from twin families, the potential influence of twinning on later health could be evaluated, independent of twin family factors.

In a cohort of bi-ethnic adolescent twins in Georgia (US) we could confirm that the previously reported inverse linear association between birth weight and blood pressure was present also in African Americans, and independent of familial factors. The findings support a role for fetal programming in African Americans that warrants further tracking of the association into adulthood.

Associations between birth weight and adult outcomes were further studied in a cohort of like-sexed twins of the Swedish Twin Register, born 1926 to 1958. First the previously reported positive association between birth weight and breast cancer was investigated in over 11 000 female twins. A linear association (from 2,500 grams and upward) was noted for the log-rate of breast cancer diagnosed before the age of 50 among unrelated twins as well as within twin pairs, indicating that the intrauterine experience may play a role in the development of early onset breast cancer. Next we performed conditional logistic regression on all twin pairs discordant for cardiovascular disease (N=1942), finding birth weight inversely associated with coronary heart disease and stroke within dizygotic (DZ) but not within monozygotic (MZ) twin pairs. Understanding which factors are shared within MZ but not DZ twin pairs could help shed some light on the underlying mechanisms to the association between birth weight and cardiovascular disease.

Lastly, we compared cumulative risks of cardiovascular disease, overall cancer and death in twins, singletons from twin families as well as from the population (identified in the Multi-Generation Register and born between 1932-1958). For all three outcomes twins appeared similar to singletons of twin families, and these in turn were not found any different from singletons of non-twin families overall.

The findings indicate that the unique experience of twinning does not influence risk of adult morbidity or mortality compared to the general population.

List of scientific papers

I. Oberg S, Ge D, Cnattingius S, Svensson A, Treiber FA, Snieder H, Iliadou A. Ethnic differences in the association of birth weight and blood pressure - The Georgia Cardiovascular Twin Study. Am J Hypertens. 2007 Dec; 20(12):1235X41.
https://doi.org/10.1016/j.amjhyper.2007.07.012

II. Oberg S, Cnattingius S, Sandin S, Lichtenstein P, Iliadou A. Birth weight – breast cancer revisited: is the association confounded by family factors. Cancer Epidemiol Biomarkers Prev. 2009 Sep; 18(9):2447-52.
https://doi.org/10.1158/1055-9965.EPI-09-0123

III. Oberg S, Cnattingius S, Sandin S, Lichtenstein P, Iliadou AN. Birth weight predicts risk of CVD within DZ but not MZ twin pairs: a large population-based co-twin-control study. Circulation. 2011. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/21632494

IV. Oberg S, Cnattingius S, Sandin S, Lichtenstein P, Morley R, Iliadou AN. Twinship influence on morbidity and mortality across the lifespan. [Manuscript]