Small for gestational age and risk of childhood mortality: A Swedish population study

Abstract

Background

Small 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 findings

In 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.

Conclusions

We 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.

Abstract

Leveraging a sibling-controlled design, Jonas Ludvigsson and colleagues examine whether SGA is associated with an increased risk of childhood death beyond the neonatal period in Sweden, and describe the most common causes of death in affected children.

Author summary

Why was this study done?

• Small for gestational age (SGA) occurs in more than 30 million infants every year.

• SGA has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce.

What did the researchers do and find?

• We evaluated the association between SGA and mortality from 28 days after birth to 18 years of age, using both general population and sibling comparators in more than 3.7 million Swedish children over a period of 40 years.

• Compared with non-SGA children, children born with severe SGA had an increased risk of death throughout childhood in both the population- and sibling-based analyses.

• The greatest risk increase associated with severe SGA was noted for deaths due to infection and neurologic disease.

• Similar but weaker associations were found for moderate SGA.

What do these findings mean?

• Our findings provide insights on associations between SGA and causes of death in childhood. SGA cannot be reversed, and hence primary preventive strategies are needed to decrease the long-term risks of intrauterine growth restriction.

• Even if absolute risks are low, an opportunity to reduce the harms of SGA may exist in infectious disease prevention and treatment.