Developmental Origins of Disease: Influence of low birth weight and maternal vitamin A and D status on offspring skeletal health and metabolic outcomes at adulthood
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Developmental origins of adult health and disease (DOHaD) has gained increased attention during the past few decades. Birth size reflects the prenatal environment, and there is substantial evidence that low birth weight (LBW) is related to a greater risk of cardiometabolic comorbities, such as hypertension, insulin resistance, dyslipidemia, obesity and osteoporosis. The survival rate of premature infants has increased dramatically and is estimated to be over 95% today. A substantial number of infants are also born small for gestational age (SGA) at term. Whether these infants have a similar risk for adverse health effects as those born preterm with LBW is not established. This thesis is based on two cohorts followed up from birth in 1986-1988 to adulthood. The aims were to study the influence of LBW on skeletal health and metabolic outcomes at the age of 26-28 years. Moreover, we wanted to explore the associations between maternal vitamin A and D status during pregnancy and offspring bone health. In paper 1, we studied skeletal parameters at the age of peak bone mass in two groups with LBW, namely adults born preterm with very low birth weight (VLBW) (Cohort 1) and SGA at term (Cohort 2) compared with term-born controls with normal birth weight (Cohort 2).We examined bone mineral content (BMC), bone mineral density (BMD) and trabecular bone score (TBS) by dual x-ray absorptiometry. Both LBW groups and especially the VLBW group displayed lower BMC and BMD than controls. Adjusted odds ratios for osteopenia/osteoporosis were 2.4 and 2.0 in VLBW and SGA adults, respectively. TBS, which is a measure of bone quality, did not differ between groups. Serum Dickkopf-related protein 1 was higher in VLBW subjects’ vs controls, indicating inhibition of bone formation. However, it was not significant after adjustment for multiple comparisons. In Paper II, we examined the association between LBW and metabolic outcomes at adulthood (25-28 years) in the same population (including three more individuals) as in paper I. We applied the criteria from the Joint Interim Statement of the International Diabetes Federation for metabolic syndrome (MetS). Outcomes were indices of MetS: waist circumference, BP, fasting glucose, lipid profile. We used a calculated MetS score as a tool to assess the relationship between MetS and skeletal health (BMD and TBS). We observed a less favorable profile in VLBW individuals, and preferentially in females. This group displayed higher systolic and diastolic BP, higher glycated hemoglobin and C- peptide, increased insulin resistance, and lower HDL-cholesterol. Significant differences were mainly seen between VLBW females and control females. Females in the term-born SGA group had higher waist-hip ratio, and higher total and LDL-cholesterol compared with control females, whereas the males in this group exhibited higher fasting blood glucose than did control males. At least one feature of the MetS was present in a higher proportion of VLBW participants compared with controls. This is of significance, as the presence of one component implies enhanced risk of MetS in the future. MetS score correlated positively with BMD and inversely with TBS. When stratifying for sex, significant associations were found only in males. Paper III included 41 mother-child pairs from Cohort 2.We assessed the associations between maternal serum vitamin A (retinol), 25-hydroxyvitamin D and 1,25-hydroxyvitamin D levels and offspring skeletal health at the age of 26 years. Blood samples were collected at three time-points in pregnancy (gestational week 17, 34 and 37) and in cord blood. After adjustment, we observed a positive association between average maternal serum retinol level during pregnancy and offspring lumbar spine BMD and TBS. Further, we observed associations between maternal 25-hydroxyvitamin D level in gestational week 17 and offspring femoral neck, total hip and whole body BMD. No association with maternal 1,25-hydroxyvitamin D could be revealed, and no correlations between vitamin levels in cord blood and offspring bone health were observed. In conclusion, both LBW groups, and preferentially the VLBW group, had suboptimal peak bone mass and, displayed a less favorable metabolic profile than did controls. This may imply an increased future risk for osteoporosis and MetS. The inverse association observed between MetS score and TBS indicates increased susceptibility to fracture with worsening of the metabolic profile. Finally, we show for the first time that maternal vitamin A inadequacy in pregnancy may affect offspring peak bone mass and bone quality adversely. We also confirm a positive association between maternal vitamin D status and offspring peak bone mass as reported previously, implying increased future osteoporosis risk.