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Original Investigation |

Preterm Birth and Mortality and Morbidity:  A Population-Based Quasi-experimental Study

Brian M. D’Onofrio, PhD1; Quetzal A. Class, BS1; Martin E. Rickert, PhD1; Henrik Larsson, PhD2; Niklas Långström, MD, PhD2; Paul Lichtenstein, PhD2
[+] Author Affiliations
1Department of Psychological and Brain Sciences, Indiana University–Bloomington
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
JAMA Psychiatry. 2013;70(11):1231-1240. doi:10.1001/jamapsychiatry.2013.2107.
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Importance  Preterm birth is associated with increased mortality and morbidity. However, previous studies have been unable to rigorously examine whether confounding factors cause these associations rather than the harmful effects of being born preterm.

Objective  To estimate the extent to which the associations between early gestational age and offspring mortality and morbidity are the result of confounding factors by using a quasi-experimental design, the sibling-comparison approach, and by controlling for statistical covariates that varied within families.

Design, Setting, and Participants  A population-based cohort study, combining Swedish registries to identify all individuals born in Sweden from 1973 to 2008 (3 300 708 offspring of 1 736 735 mothers) and link them with multiple outcomes.

Main Outcomes and Measures  Offspring mortality (during infancy and throughout young adulthood) and psychiatric (psychotic or bipolar disorder, autism, attention-deficit/hyperactivity disorder, suicide attempts, substance use, and criminality), academic (failing grades and educational attainment), and social (partnering, parenthood, low income, and social welfare benefits) outcomes through 2009.

Results  In the population, there was a dose-response relationship between early gestation and the outcome measures. For example, extreme preterm birth (23-27 weeks of gestation) was associated with infant mortality (odds ratio, 288.1; 95% CI, 271.7-305.5), autism (hazard ratio [HR], 3.2; 95% CI, 2.6-4.0), low educational attainment (HR, 1.7; 1.5-2.0), and social welfare benefits (HR, 1.3; 1.2-1.5) compared with offspring born at term. The associations between early gestation and mortality and psychiatric morbidity generally were robust when comparing differentially exposed siblings and controlling for statistical covariates, whereas the associations with academic and some social problems were greatly or completely attenuated in the fixed-effects models.

Conclusions and Relevance  The mechanisms responsible for the associations between preterm birth and mortality and morbidity are outcome-specific. Associations between preterm birth and mortality and psychiatric morbidity are largely independent of shared familial confounds and measured covariates, consistent with a causal inference. However, some associations, particularly predicting suicide attempt, educational attainment, and social welfare benefits, are the result of confounding factors. The findings emphasize the importance of both reducing preterm birth and providing wraparound services to all siblings in families with an offspring born preterm.

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Figure 1.
Model Fitting Results for the Association Between Gestational Age and Offspring Mortality

The bars indicate the results of the ordinal analyses for the baseline association between gestational age and the indices of offspring mortality (the analyses did not control for confounding factors). The bars represent the magnitude of increased risk from being born earlier compared with offspring born at term, with the 95% CIs represented by the error bars. The solid black line indicates the association of the best-fit model (either the linear or quadratic model) for the baseline model, considering gestational age as a continuous measure (referenced at 40 weeks of gestation). The dashed line indicates the results of the analyses that included measured covariates to account for confounding factors. The dotted line indicates the results of the analyses that used fixed-effects models that compared differentially exposed siblings and controlled for statistical covariates. Therefore, the dotted line indicates the increased risk associated with early gestational age when accounting for all genetic and environmental factors that make siblings similar and the statistical covariates that varied within families. The 95% confidence region of the association between gestational age and each offspring outcome in the fixed-effects model is shaded.

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Figure 2.
Model Fitting Results for the Association Between Gestational Age and Psychiatric Morbidity

The shaded bars indicate the results of the ordinal analyses for the baseline association between gestational age and the indices of offspring psychiatric morbidity (the analyses did not control for confounding factors). See Figure 1 caption for further explanation. ADHD indicates attention-deficit/hyperactivity disorder.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Model Fitting Results for the Association Between Gestational Age and Social Adversity

The shaded bars indicate the results of the ordinal analyses for the baseline association between gestational age and the indices of offspring social adversity (the analyses did not control for confounding factors). See Figure 1 caption for further explanation.

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