Low birth weight and risk of chronic disease: lessons from twins Sven Cnattingius, MD, PhD Unit of Clinical Epidemiology Department of Medicine Karolinska Institutet Stockholm, Sweden Low birth weight (a measure of fetal growth restriction) influence risk of adult disease. Is this due to: Fetal programming? Genetic factors? Early environmental factors? Other explanations? Genetic confounding Simplified pathway Nutrition during pregnancy Fetal conditions Birth weight Adult disease Socioeconomic factors Genes Birth weight Socioeconomic confounding Genetics and fetal growth: Risk of Small-for-Gestational-Age (SGA) births to parents who are siblings OR (95% CI) Full sisters 1.8 (1.7-1.9) Half sisters 1.2 (1.1-1.4) Full brothers 1.3 (1.2-1.4) Half brothers 1.1 (0.9-1-4) Svensson Am J Obstet Gynecol 2006 Genetic contribution to SGA: Analyses of family data Maternal contribution: -maternal genetic 9% -fetal genetic 19% Paternal contribution -fetal genetic 19% Total genetic contribution 47% Svensson Am J Obstet Gynecol 2006 Social factors in early life Influence fetal growth Influence risks of chronic diseases later in life However, studies have found associations between birth weight and adult disease independent of social factors in early life but…. ….it is difficult to control for social factors - an example: Maternal smoking and risk of poor school performance in offspring Maternal smoking (cig./day) Adjusted Odds Ratio 0 1.00 1-9 1.58 >10 1.89 Lambe et al. Epidemiology 2006 Maternal smoking and risk of poor school performance in offspring Mother’s smoking (cig/day) Mother’s smoking (cig/day) Odds Ratio Odds Ratio 1st pregnancy 2nd pregnancy 1st birth 2nd birth 0 0 1.00 1.00 1-9 0 1.24 1.41 >10 0 1.59 1.83 >10 >10 1.79 2.11 Lambe et al. Epidemiology 2006 What is the added value of twin studies? MZ and DZ twins Fraternal, DZ, (from 2 eggs) average genetic sharing 50% Identical, MZ (from a single embryo) genetic sharing 100% Twins_Poster Fetal growth and adult disease Is the association mediated by…? Intrauterine growth External comparisons Yes Within DZ twins Yes Within MZ twins Yes Fetal growth and adult disease Is the association mediated by…? Intrauterine growth Genetic factors External comparisons Yes Yes Within DZ twins Yes Partly Within MZ twins Yes No Fetal growth and adult disease Is the association mediated by…? Intrauterine Growth Genetic factors Shared early environment External comparisons Yes Yes Yes Within DZ twins Yes Partly No Within MZ twins Yes No No Other advantages Differences in birth weight within twin pairs reflect differences in fetal growth Differences in birth weight within MZ twin pairs reflect differences in fetal growth exclusively due to intrauterine environment Fetal growth discordance is common within twin pairs Birth weight differences in our cohort of surviving twins: 240 grams in MZ twin pairs; 290 grams in DZ twin pairs. Fetal growth discordance is common within twin pairs 31% of term twin pairs have a birth weight difference of at least 400 grams 10% of all twin pairs have a birth weight difference of at least 25% Can you generalize from twin studies to singletons? Does being a twin influence adult health? C:\Users\svecna\Pictures\fantomen\1056419-z2_super[1].jpg Twins and their singleton siblings: No differences in cardiovascular morbidity Öberg, Int J Epidemiol 2012 Twins and their singleton siblings: No overall differences in cancer morbidity Öberg, Int J Epidemiol 2012 Twins and their singleton siblings: No differences in mortality by age Öberg, Int J Epidemiol 2012 Twin and singleton families: No differences in mortality Öberg, Int J Epidemiol 2012 However… ”the third trimester may represent the vulnerable period for fetal programming.” Twins have: Shorter gestational age; Earlier onset of fetal growth restriction Gestational age in a cohort of 24,332 like-sexed Swedish twins born 1926-58 Gestational age (weeks) Twins (%) 31-34 13 35-36 20 37-41 58 42-45 3 missing 6 50th birth weight percentile by singletons, twins and triplets (United States) twin growth Thus, Most twins are born in the 3rd trimester Twins are commonly exposed to fetal growth restriction in the 3rd trimester Dizygotic twins Have two placentas Have two amniotic sacs Differences in birth weight reflect differences in fetal growth due to placental function Monozygotic twins 70% share placenta (i.e., are monochorionic) Unequal sharing of placental blood flow is the major contributor to birth weight discordance also within monochorionic MZ twins but…. ...Monozygotic twins may suffer from twin-twin transfusion syndrome (TTTS) twins50 TTTS may result in large differences in fetal growth TTTS03 Severe twin-to-twin transfusion syndrome: is it a problem? Monozygotic Twins Dichorionic ( ≈ 30 % ) Monochorionic ( ≈ 70 % ) Normal Placental IUGR TTTS ( ≈ 10-15 % of all pregnancies) Twin A: IUGR Twin B: Cardiac overload Characteristics of TTTS Twins: Perinatal mortality rates when left untreated: 50 – 100 % Uncommon with two survivors in a pair when TTTS is left untreated. Up to 90 % of TTTS pregnancies are delivered preterm. Even when treated, up to 25 % of TTTS survivors have cerebral palsy. …..for a cohort born before 1958, probably not.. Twins born 1926-58 with known zygosity Nation-wide data collection of birth data Birth data recorded by midwives at the time of delivery Birth weight available in: 10,226 MZ and 15,965 DZ like-sexed twins 5,111 MZ and 7,973 DZ like-sexed twin pairs Birth weight and risk of hypertension OR cohort 500 grams decrease in birth weight 1.42* Bergvall et al. Circulation 2007 Birth weight and risk of hypertension Analyses within twin siblings Analyses within twin siblings cohort DZ 500 grams decrease in birth weight 1.42* 1.34* Bergvall et al. Circulation 2007 Birth weight and risk of hypertension cohort Analyses within twin siblings Analyses within twin siblings DZ MZ 500 grams decrease in birth weight 1.42* 1.34* 1.74* Bergvall et al. Circulation 2007 Birth weight and risk of type 2 diabetes OR cohort 500 grams decrease in birth weight 1.34* Johansson et al. Epidemiology 2007 Birth weight and risk of type 2 diabetes Analyses within twin siblings Analyses within twin siblings cohort DZ 500 grams decrease in birth weight 1.44* 1.38* Johansson et al. Epidemiology 2008 Birth weight and risk of type 2 diabetes Analyses within twin siblings Analyses within twin siblings cohort DZ MZ 500 grams decrease in birth weight 1.44* 1.38* 1.02 Johansson et al. Epidemiology 2008 Birth weight and risk of coronary heart disease Dizygotic Monozygotic Birth weight OR OR <2499 1.37 0.85 2500-2999 1.27 0.79 >3000 1.00 1.00 Öberg et al. Circulation 2011 Birth weight and risk of stroke Dizygotic Monozygotic Birth weight OR OR <2499 2.03* 0.76 2500-2999 1.19 1.19 >3000 1.00 1.00 Öberg et al. Circulation 2011 Birth weight and risk of ischaemic stroke Dizygotic Monozygotic Birth weight OR OR <2499 2.04* 0.49 2500-2999 1.02 0.50 >3000 1.00 1.00 Öberg et al. Circulation 2011 Birth weight and risk of hemorrhagic stroke Dizygotic Monozygotic Birth weight OR OR <2499 1.59 1.56 2500-2999 1.57 1.57 >3000 1.00 1.00 Öberg et al. Circulation 2011 Conclusions Differences in birth weight within MZ twins reflect differences in fetal growth Twins and singletons have similar adult morbidity and mortality In twin studies, there is little support for an association between fetal growth and CVD in the absence of genetic variation. Acknowledgements Co-workers Funding Swedish Research Council Swedish Cancer Society Swedish Council for Working Life and Social Support European Union Centre of Excellence ”Life-span” Niklas_Paul_Tassa_Stefan_3 Oberg_Sara Niklas Bergvall, Paul Lichtenstein, Anastasia Iliadou, Stefan Johansson and Sara Öberg