Fetal programming: the perspective of single and twin pregnancies

Multiple pregnancy is associated with increased risk of adverse consequences for both mother and fetus(es), including increased rates of maternal hypertension and pre-eclampsia, spontaneous abortion, Caesarean delivery, low birthweight, birth prematurity, perinatal mortality, admission to neonatal intensive care and extended length of care, respiratory distress, cerebral palsy, developmental delay, contact with disability services and mortality to age 5 years. Premature birth, which affects 97% of triplets and 53.3% of twins in Australia, is not the sole factor involved. The rate of multiple pregnancy in Australia is 1.7%. This compares to 22.1% for pregnancies resulting from assisted reproduction technology (ART). As a result, 21.8% of babies born from ART are from a multiple pregnancy, in comparison to the USA where the majority of babies born from ART are from a multiple pregnancy. Additionally, the population rate of multiple births is rising due to the more frequent use of ART and continued multi-embryo transfers, which is operating against a background of rising implantation rates within ART clinics. Twins have been of interest from a programming perspective. However, analysis of associations between crude birthweight and subsequent metabolic risk factors or mortality in adulthood from chronic disease indicate that adaptations in pregnancy to support multi-fetal growth are not identical to fetal growth restriction in singleton pregnancies. Indeed, the process of 'maternal constraint' is incompletely understood and confounds such comparisons. From a programming perspective, it is a challenge to identify in twin pregnancies the transition from physiological adaptation to pathological growth restriction. Growth disparity between twins has been more illuminating of subtle adverse effects for the smaller of twin pairs in both blood pressure and insulin resistance in adulthood. Interestingly, these effects can be observed in both dizygotic and to a lesser degree in monozygotic twins, which indicates a role for both genetic and environmental factors in these measures. This suggests that, consistent with experimental studies in other species, the relationship between impaired growth in utero and chronic disease in later life is not simply mediated by a common genetic pathway.