Many paediatric clinical research studies, whether observational or interventional, have as an eventual aim the identification or quantification of causal relationships. One might ask: does screen time influence childhood obesity? Could overuse of paracetamol in infancy cause wheeze? How does breastfeeding affect later cognitive outcomes? In this review, we present causal Directed Acyclic Graphs (DAGs) to a paediatric audience. DAGs are a graphical tool which provide a way to visually represent and better understand the key concepts of exposure, outcome, causation, confounding, and bias. We use clinical examples, including those outlined above, framed in the language of DAGs, to demonstrate their potential applications. We show how DAGs can be most useful in identifying confounding and sources of bias, demonstrating inappropriate statistical adjustments for presumed biases, and understanding threats to validity in randomised controlled trials. We believe that a familiarity with DAGs, and the concepts underlying them, will be of benefit both to researchers planning studies, and practicing clinicians interpreting them.

Three subtypes of CHD were associated with lower placental weight, and placental weight was associated with measures of both overall growth and cerebral growth in fetuses with all subtypes of CHD. In certain subtypes, the described deviations in fetal growth were reduced by up to two-thirds after adjustment for placental weight z score.

Background:Previous studies indicated an association between intrauterine exposure to perfluorooctane sulfonate (PFOS) or perfluorooctanoate (PFOA) and lower birth weight. However, these perfluoroalkyl acids (PFAAs) have to some extent been substituted by other compounds on which little is known.Objectives:We investigated the association between specific PFAAs and birth weight, birth length, and head circumference at birth.Methods:We studied 1,507 mothers and their children from the Aarhus Birth Cohort (2008–2013). Nulliparous women were included during pregnancy, and serum levels of 16 PFAAs were measured between 9 and 20 completed gestational weeks (96% within 13 weeks). For compounds with quantifiable values in > 50% of samples (7 compounds), we report the associations with birth weight, birth length, and head circumference at birth determined by multivariable linear regression.Results:Estimated mean birth weights were lower among women with serum perfluorohexane sulfonate, perfluoroheptane sulfonate, and PFOS concentrations above the lowest exposure quartile, but we found no consistent monotonic dose–response patterns. These associations were stronger when the population was restricted to term births (n = 1,426). For PFOS, the birth weight estimates for the highest versus lowest quartile were –50 g (95% CI: –123, 23 g) in all births and –62 g (95% CI: –126, 3 g) in term births. For the other PFAAs, the direction of the associations was inconsistent, and no overall association with birth weight was apparent. No PFAAs were associated with birth length or head circumference at birth.Conclusions:Overall, we did not find strong or consistent associations between PFAAs and birth weight or other indices of fetal growth, though estimated mean birth weights were lower among those with exposures above the lowest quartile for some compounds.Citation:Bach CC, Bech BH, Nohr EA, Olsen J, Matthiesen NB, Bonefeld-Jørgensen EC, Bossi R, Henriksen TB. 2016. Perfluoroalkyl acids in maternal serum and indices of fetal growth: the Aarhus Birth Cohort. Environ Health Perspect 124:848–854; http://dx.doi.org/10.1289/ehp.1510046

Background— Neurodevelopmental disorders are the most common and distressful comorbidities associated with congenital heart defects (CHD). Head circumference at birth (HC), a proxy for prenatal cerebral growth, is an established risk factor for neurodevelopmental disorders. Methods and Results— In a nationwide cohort, we included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 5519. The association between CHD and growth indices was analyzed by multivariable linear regression, adjusted for potential confounders. We report mean differences in gestational age–specific z scores in comparison with the general population. CHD was associated with lower HC z scores, –0.10 (95% confidence interval [CI], –0.13 to –0.08). Several CHD subtypes were associated with smaller HC, eg, hypoplastic left heart syndrome, –0.39 (95% CI, –0.58 to –0.21); common arterial trunk, –0.41 (95% CI, –0.74 to –0.09); and major ventricular septal defects, –0.25 (95% CI, –0.35 to –0.15). Other single-ventricle defects, transposition of the great arteries, tetralogy of Fallot, and anomalous pulmonary venous return, were also associated with smaller HC. Transposition of the great arteries was associated with smaller HC relative to birth weight, –0.26 (95% CI, –0.39 to –0.13). Major ventricular septal defects were associated with larger HC relative to birth weight. The results were consistent under various conditions, eg, when siblings of infants with CHD (n=5311) or infants with other major malformations (n=24 974) were used as the reference. Conclusions— Several subtypes of CHD were associated with smaller HC. The associations with major ventricular septal defects, common arterial trunk, and anomalous pulmonary venous return have not previously been described. Only infants with transposition of the great arteries had smaller HC relative to birth weight.

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Our findings indicate that fetal cerebral T2* is measurable and that fetal cerebral tissue oxygenation measured by T2* is lower in fetuses with heart defects compared with fetuses without heart defects. This corroborates the hypothesis that tissue hypoxia may be a potential pathogenic factor that possibly affects brain development in fetuses with heart defects.

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No association between fertility treatment and childhood type 1 diabetes mellitus was found. Ovulation induction or intrauterine insemination with follicle-stimulating hormone may be associated with an increased risk of childhood type 1 diabetes mellitus. However, this finding may be due to chance or to confounding by indication and thus requires further investigation.