Date Published: December 18, 2018
Publisher: Public Library of Science
Author(s): Jonas F. Ludvigsson, Donghao Lu, Lennart Hammarström, Sven Cnattingius, Fang Fang, Gordon C. Smith
Abstract: BackgroundSmall for gestational age (SGA) has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce. Maternal antenatal care, including globally reducing the risk of SGA birth, may be key to achieving the Millennium Development Goal of reducing under-5 mortality. We therefore aimed to examine the association between SGA and mortality from 28 days to <18 years using a population-based and a sibling control design.Methods and findingsIn a Swedish population study, we identified 3,795,603 non-malformed singleton live births and 2,781,464 full siblings born from January 1, 1973, to December 31, 2012. We examined the associations of severe (<3rd percentile) and moderate (3rd to <10th percentile) SGA with risks of death from 28 days to <18 years after birth. Children born SGA were first compared to non-SGA children from the population, and then to non-SGA siblings. The sibling-based analysis, by design, features a better control for unmeasured factors that are shared between siblings (e.g., socioeconomic status, lifestyle, and genetic factors). Hazard ratios (HRs) were calculated using Cox proportional hazards and flexible parametric survival models. During follow-up (1973–2013), there were 10,838 deaths in the population-based analysis and 1,572 deaths in sibling pairs with discordant SGA and mortality status. The crude mortality rate per 10,000 person-years was 5.32 in children born with severe SGA, 2.76 in children born with moderate SGA, and 1.93 in non-SGA children. Compared with non-SGA children, children born with severe SGA had an increased risk of death in both the population-based (HR = 2.58, 95% CI = 2.38–2.80) and sibling-based (HR = 2.61, 95% CI = 2.19–3.10) analyses. Similar but weaker associations were found for moderate SGA in the population-based (HR = 1.37, 95% CI = 1.28–1.47) and sibling-based (HR = 1.38, 95% CI = 1.22–1.56) analyses. The excess risk was most pronounced between 28 days and <1 year of age but remained throughout childhood. The greatest risk increase associated with severe SGA was noted for deaths due to infection and neurologic disease. Although we have, to our knowledge, the largest study sample so far addressing the research question, some subgroup analyses, especially the analysis of cause-specific mortality, had limited statistical power using the sibling-based approach.ConclusionsWe found that SGA, especially severe SGA, was associated with an increased risk of childhood death beyond the neonatal period, with the highest risk estimates for death from infection and neurologic disease. The similar results obtained between the population- and sibling-based analyses argue against strong confounding by factors shared within families.
Partial Text: The Barker hypothesis proposes that intrauterine growth restriction may cause cardiovascular disease in middle and old age [1–3]. Some data indicate that fetal growth may also influence other diseases in adulthood [4,5], although confounding remains an issue .
In this population study of more than 3.7 million children we found that severe SGA (<3rd percentile) was associated with increased mortality from 28 days to <18 years of life. Moderate SGA (3rd to <10th percentile) was associated with more modestly increased mortality within the first 10 years of life. The similar results between the population- and sibling-based analyses argue against strong confounding by familial factors. Given the high prevalence of SGA, our findings have important public health implications and underline the need to tackle long-term consequences of SGA. Source: http://doi.org/10.1371/journal.pmed.1002717