Preterm birth and mortality and morbidity: a population-based quasi-experimental study

Abstract

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.

Figure 1

Model Fitting Results for the Association between Gestational Age and Offspring Mortality, Psychiatric Morbidity, Academic Problems, and Social Adversity. Note. The shaded bars present the results of the ordinal analyses for the baseline association between gestational age and the indices of offspring mortality and morbidity (the analyses did not control for confounding factors). The bars represent the magnitude of increased risk from being born earlier compared to offspring born at term, with the 95% confidence intervals represented by the error bars. The solid black line presents the association of the best fitting 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 presents the results of the analyses that included measured covariates to account for confounds. The dotted line presents the results of the analyses that used fixed effects model that compared differentially exposed siblings and controlled for statistical covariates. The line, therefore, presents 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 presented in shaded blue.

Figure 1

Model Fitting Results for the Association between Gestational Age and Offspring Mortality, Psychiatric Morbidity, Academic Problems, and Social Adversity. Note. The shaded bars present the results of the ordinal analyses for the baseline association between gestational age and the indices of offspring mortality and morbidity (the analyses did not control for confounding factors). The bars represent the magnitude of increased risk from being born earlier compared to offspring born at term, with the 95% confidence intervals represented by the error bars. The solid black line presents the association of the best fitting 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 presents the results of the analyses that included measured covariates to account for confounds. The dotted line presents the results of the analyses that used fixed effects model that compared differentially exposed siblings and controlled for statistical covariates. The line, therefore, presents 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 presented in shaded blue.

Figure 1

Model Fitting Results for the Association between Gestational Age and Offspring Mortality, Psychiatric Morbidity, Academic Problems, and Social Adversity. Note. The shaded bars present the results of the ordinal analyses for the baseline association between gestational age and the indices of offspring mortality and morbidity (the analyses did not control for confounding factors). The bars represent the magnitude of increased risk from being born earlier compared to offspring born at term, with the 95% confidence intervals represented by the error bars. The solid black line presents the association of the best fitting 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 presents the results of the analyses that included measured covariates to account for confounds. The dotted line presents the results of the analyses that used fixed effects model that compared differentially exposed siblings and controlled for statistical covariates. The line, therefore, presents 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 presented in shaded blue.