Quetzal A. Class

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

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.

Timing of prenatal maternal exposure to severe life events and adverse pregnancy outcomes: a population study of 2.6 million pregnancies.

Objective: To identify the impact of timing of prenatal stress exposure on offspring risk for shortened gestational age, preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA), using a population-based sample. Methods: Swedish longitudinal population registries were linked to study all individuals born in Sweden from 1973 to 2004. Prenatal maternal stress exposure was defined as death of the father of the child or first-degree relative of the mother. Using linear and logistic regression, timing of stress exposure was examined across pregnancy, by month, and by novel periods created based on month of stress exposure findings. Results: A total of 2,618,777 live-born, singleton infants without congenital anomalies were included; 32,286 were exposed to prenatal maternal stress. Examining associations between stress exposure and outcome by the month revealed that risk increases midgestation, particularly after months 5 and 6. Combining months 1 to 4, 5 and 6, and 7 to 9 as potential periods of differing vulnerability, it was found that stress during period 2 (months 5 and 6) was associated with the greatest risk for shortened gestational age (−0.52 days, standard error = 0.15, p = .0006), PTB (odds ratio [OR], 1.24; 99% confidence interval [CI], 1.08–1.42), LBW (OR, 1.38; 99% CI, 1.19–1.61), and SGA (OR, 1.25; 99% CI, 1.05–1.49). Conclusions: Risk for shortened GA, PTB, LBW, and SGA are greater post stress exposure during the 5th and/or 6th month of pregnancy. It may be beneficial to refine future analyses to these months. Possible mechanisms include alterations in the hypothalamic-pituitary-adrenal axis and associated stress-responsive molecular regulators. CRH = corticotropin-releasing hormone; GA = gestational age; HPA = hypothalamic-pituitary-adrenal; LBW = low birth weight; PAPP-A = pregnancy-associated plasma protein-A; PTB = preterm birth; SGA = small for gestational age.

Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress

BACKGROUND Preconception, prenatal and postnatal maternal stress is associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between maternal bereavement stress and offspring autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt and completed suicide. METHOD Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992-2000 for childhood outcomes and 2,155,221 offspring born 1973-1997 for adult outcomes with follow-up to 2009. Maternal stress was defined as death of a first-degree relative during (a) the 6 months before conception, (b) pregnancy or (c) the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HRs) in unadjusted and adjusted analyses. RESULTS Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third-trimester prenatal stress increased the risk of ASD [adjusted HR (aHR) 1.58, 95% confidence interval (CI) 1.15-2.17] and ADHD (aHR 1.31, 95% CI 1.04-1.66). First postnatal year stress increased the risk of offspring suicide attempt (aHR 1.13, 95% CI 1.02-1.25) and completed suicide (aHR 1.51, 95% CI 1.08-2.11). Bereavement stress during the second postnatal year increased the risk of ASD (aHR 1.30, 95% CI 1.09-1.55). CONCLUSIONS Further research is needed regarding associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases the risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases the risk of offspring suicide attempt, completed suicide and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.

Maternal Stress and Infant Mortality The Importance of the Preconception Period

Although preconception and prenatal maternal stress are associated with adverse outcomes in birth and childhood, their relation to infant mortality remains uncertain. We used logistic regression to study infant mortality risk following maternal stress within a population-based sample of infants born in Sweden between 1973 and 2008 (N = 3,055,361). Preconception (6–0 months before conception) and prenatal (between conception and birth) stress were defined as death of a first-degree relative of the mother. A total of 20,651 offspring were exposed to preconception stress, 26,731 offspring were exposed to prenatal stress, and 8,398 cases of infant mortality were identified. Preconception stress increased the risk of infant mortality independently of measured covariates, and this association was timing specific and robust across low-risk groups. Prenatal stress did not increase risk of infant mortality. These results suggest that the period immediately before conception may be a sensitive developmental period with ramifications for infant mortality risk.

Fetal growth and psychiatric and socioeconomic problems: population-based sibling comparison

BACKGROUND It is unclear whether associations between fetal growth and psychiatric and socioeconomic problems are consistent with causal mechanisms. AIMS To estimate the extent to which associations are a result of unmeasured confounding factors using a sibling-comparison approach. METHOD We predicted outcomes from continuously measured birth weight in a Swedish population cohort (n = 3 291 773), while controlling for measured and unmeasured confounding. RESULTS In the population, lower birth weight (⩽ 2500 g) increased the risk of all outcomes. Sibling-comparison models indicated that lower birth weight independently predicted increased risk for autism spectrum disorder (hazard ratio for low birth weight = 2.44, 95% CI 1.99-2.97) and attention-deficit hyperactivity disorder. Although attenuated, associations remained for psychotic or bipolar disorder and educational problems. Associations with suicide attempt, substance use problems and social welfare receipt, however, were fully attenuated in sibling comparisons. CONCLUSIONS Results suggest that fetal growth, and factors that influence it, contribute to psychiatric and socioeconomic problems.

Translational Epidemiologic Approaches to Understanding the Consequences of Early-Life Exposures.

Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes.

Preconception Maternal Bereavement and Infant and Childhood Mortality: A Danish Population-Based Study.

Objectives Preconception maternal bereavement may be associated with an increased risk for infant mortality, although these previously reported findings have not been replicated. We sought to examine if the association could be replicated and explore if risk extended into childhood. Methods Using a Danish population-based sample of offspring born 1979 to 2009 (N = 1,865,454), we analyzed neonatal (0–28 days), postneonatal infant (29–364 days), and early childhood (1–5 years) mortality after maternal bereavement in the preconception (6-0 months before pregnancy) and prenatal (between conception and birth) periods. Maternal bereavement was defined as death of a first-degree relative of the mother. Analyses were conducted using logistic and log-linear Poisson regressions that were adjusted for offspring, mother, and father sociodemographic and health factors. Results We identified 6541 (0.004%) neonates, 3538 (0.002%) postneonates, and 2132 (0.001%) children between the ages of 1 and 5 years who died. After adjusting for covariates, bereavement during the preconception period was associated with increased odds of neonatal (adjusted odds ratio = 1.87, 95% confidence interval = 1.53–2.30) and postneonatal infant mortality (adjusted odds ratio = 1.52, 95% confidence interval = 1.15–2.02). Associations were timing specific (6 months before pregnancy only) and consistent across sensitivity analyses. Bereavement during the prenatal period was not consistently associated with increased risk of offspring mortality; however, this may reflect relatively low statistical power. Conclusions Results support and extend previous findings linking bereavement during the preconception period with increased odds of early offspring mortality. The period immediately before pregnancy may be a sensitive period with potential etiological implications and ramifications for offspring mortality.

The association between childhood relocations and subsequent risk of suicide attempt, psychiatric problems, and low academic achievement

BACKGROUND Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors. METHOD We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983-1997 (n = 1 510 463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings. RESULTS In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.19-1.20]. However, when accounting for offspring and parental covariates (HR 1.08, 95% CI 1.07-1.09), as well as genetic and environmental confounds shared by cousins (HR 1.07, 95% CI 1.05-1.09) and siblings (HR 1.00, 95% CI 0.97-1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement. CONCLUSIONS Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality.

Exploring the heterogeneity in clinical presentation and functional impairment of postpartum depression

Objective: Examine the spectrum of postpartum psychiatric conditions with the aim to evaluate the current use of a postpartum onset specifier. Background: The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) uses an onset specifier to categorise a limited number of psychiatric diagnoses as postpartum onset. Diagnoses and clinical symptomatology, however, may be more complex than what the DSM-IV-TR allows. Methods: A total of 59 women aged 19–41 years were recruited 3–6 months postpartum. Women completed questionnaires and those scoring possibly depressed, identified by scoring at least 10 (30 maximum) on the Edinburgh Postnatal Depression Scale, participated in semi-structured psychiatric evaluations. Degree of functional impairment was rated on a three-point scale. Results: Possibly depressed women did not differ from healthy controls on several background characteristics. Postpartum diagnoses were heterogeneous; only 46% of possibly depressed women received a diagnosis of major depression. Other diagnoses included depressive disorder not otherwise specified, adjustment disorder, anxiety disorder not otherwise specified, alcohol dependence, and two women did not qualify for a diagnosis. Functional impairment did not differ across diagnoses. A diathesis-stress perspective aided understanding of the clinical expression of psychopathology and creating clinical case formulations. Conclusions: The limited application of a postpartum onset specifier is unsatisfactory. Unless the diverse range of postpartum disorders is properly acknowledged by considering a diathesis–stress perspective and allowing for an onset specifier, the care of women experiencing psychological distress during the postpartum period may have reduced effectiveness and future research will be hindered.

Neurobehavioral Disorders and Developmental Origins of Health and Disease

Abstract The human fetus is an active participant in its own development by integrating information received from its maternal host into its neurodevelopmental program to prepare for life after birth. Because the fetal nervous system develops at precise times and in a specific sequence from conception to birth, disruption by intrauterine events in the timing or sequence of brain development results in tissue remodeling. Depending on the timing of the disruption, the function and physiological capacity of the remodeled brain is affected throughout the lifespan. Evidence from prospective and retrospective studies supports the conclusion that fetal exposures to maternal signals of psychobiological stress or being born small or early are associated with increased risk for behavioral disorders and alterations in brain structures in children and adults. A range of early-life exposures results in similar neurobehavioral “programs” suggesting a common neural mechanism. Alteration in dendritic tree complexity is one plausible mechanism that mediates the relation between fetal exposure to stress and neurobehavioral programming.