Associations between low birth weight (=2,500 g) and increased risk of mortality and morbidity provided the foundation for the "developmental origins of health and disease" hypothesis. Previous between-family studies could not control for unmeasured confounders. Therefore, we compared differentially exposed siblings to estimate the extent to which the associations were due to uncontrolled factors. Our population cohort included 3,291,773 persons born in Sweden from 1973 to 2008. Analyses controlled for gestational age, among other covariates, and considered birth weight as both an ordinal and a continuous variable. Outcomes included mortality after 1 year, cardiac-related death, hypertension, ischemic heart disease, pulmonary circulation problems, stroke, and type 2 diabetes mellitus. We fitted fixed-effects models to compare siblings and conducted sensitivity analyses to test alternative explanations. Across the population, the lower the birth weight, the greater the risk of mortality (e.g., cardiac-related death (low birth weight hazard ratio = 2.69, 95% confidence interval: 2.05, 3.53)) and morbidity (e.g., type 2 diabetes mellitus (low birth weight hazard ratio = 1.79, 95% confidence interval: 1.50, 2.14)) outcomes in comparison with normal birth weight. All associations were independent of shared familial confounders and measured covariates. Results emphasize the importance of birth weight as a risk factor for subsequent mortality and morbidity.
A genetically-informed, quasi-experimental design was used to examine the genetic and environmental processes underlying associations between current parental depressive symptoms and offspring perceived self-competence. Participants, drawn from a population-based Swedish sample, were 852 twin pairs and their male (52 %) and female offspring aged 15.7 ± 2.4 years. Parental depressive symptoms were measured using the Center for Epidemiological Studies Depression scale. Offspring perceived self-competence was measured using a modified Harter Perceived Competence Scale. Cousin comparisons and Children of Twins designs suggested that associations between maternal depressive symptoms and offspring perceived self-competence were due to shared genetic/environmental liability. The mechanism responsible for father-offspring associations, however, was independent of genetic factors and of extended family environmental factors, supporting a causal inference. Thus, mothers and fathers may impact offspring perceived self-competence via different mechanisms and unmeasured genetic and environmental selection factors must be considered when studying the intergenerational transmission of cognitive vulnerabilities for depression.
We examined associations of maternal age at childbearing (MAC) with gestational age and fetal growth (i.e., birth weight adjusting for gestational age), using two genetically informed designs (cousin and sibling comparisons) and data from two cohorts, a population-based Swedish sample and a nationally representative United States sample. We also conducted sensitivity analyses to test limitations of the designs. The findings were consistent across samples and suggested that, associations observed in the population between younger MAC and shorter gestational age were confounded by shared familial factors; however, associations of advanced MAC with shorter gestational age remained robust after accounting for shared familial factors. In contrast to the gestational age findings, neither early nor advanced MAC was associated with lower fetal growth after accounting for shared familial factors. Given certain assumptions, these findings provide support for a causal association between advanced MAC and shorter gestational age. The results also suggest that there are not causal associations between early MAC and shorter gestational age, between early MAC and lower fetal growth, and between advanced MAC and lower fetal growth.
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.
Parental severe mental illness (SMI) is associated with an increased risk of offspring autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). We conducted a study to examine the extent to which risk of preterm birth, low birth weight, and small for gestational age mediated this association.
We obtained data on offspring born 1992-2001 in Sweden (n = 870,017) through the linkage of multiple population-based registers. We used logistic and Cox regression to assess the associations between parental SMI, adverse pregnancy outcomes, and offspring ASD and ADHD, as well as tested whether adverse pregnancy outcomes served as mediators.
After controlling for measured covariates, maternal and paternal SMI were associated with an increased risk for preterm birth, low birth weight, and gestational age, and for offspring ASD and ADHD. These pregnancy outcomes were also associated with an increased risk of ASD and ADHD. We found that pregnancy outcomes did not mediate the association between parental SMI and offspring ASD and ADHD, as there was no substantial change in magnitude of the risk estimates after controlling for pregnancy outcomes.
Parental SMI and adverse pregnancy outcomes appear to be independent risk factors for offspring ASD and ADHD.
Causal interpretation of associations between short interpregnancy interval (the duration from the preceeding birth to the conception of the next-born index child) and the offspring's psychological and educational problems may be influenced by a failure to account for unmeasured confounding.
Using population-based Swedish data from 1973-2009, we estimated the association between interpregnancy interval and outcomes [autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), severe mental illness, suicide attempt, criminality, substance-use problem and failing grades] while controlling for measured covariates. We then used cousin comparisons, post-birth intervals (the interval between the second- and third-born siblings to predict second-born outcomes) and sibling comparisons to assess the influence of unmeasured confounding. We included an exploratory analysis of long interpregnancy interval.
Interpregnancy intervals of 0-5 and 6-11?months were associated with higher odds of outcomes in cohort analyses. Magnitudes of association were attenuated following adjustment for measured covariates. Associations were eliminated for ADHD, severe mental illness and failing grades, but maintained magnitude for ASD, suicide attempt, criminality and substance-use problem in cousin comparisons. Post-birth interpregnancy interval and sibling comparisons suggested some familial confounding. Associations did not persist across models of long interpregnancy interval.
Attenuation of the association in cousin comparisons and comparable post-birth interval associations suggests that familial genetic or environmental confounding accounts for a majority of the association for ADHD, severe mental illness and failing grades. Modest associations appear independently of covariates for ASD, suicide attempt, criminality and substance-use problem. Post-birth analyses and sibling comparisons, however, show some confounding in these associations.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.