Martin E. Rickert

Paternal age at childbearing and offspring psychiatric and academic morbidity

IMPORTANCE Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors. OBJECTIVE To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity. DESIGN, SETTING, AND PARTICIPANTS We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins. EXPOSURE Paternal age at childbearing. MAIN OUTCOMES AND MEASURES Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity. RESULTS In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings. CONCLUSIONS AND RELEVANCE Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

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.

Disinhibitory Psychopathology and Delay Discounting in Alcohol Dependence: Personality and Cognitive Correlates

Increased discounting of delayed rewards may reflect a decision bias that contributes to excessive use of alcohol and more generally, to an impulsive, disinhibitory predisposition that is characterized by a preference for immediate over long-term rewards. The current study examined the association between delay discounting of rewards and the covariation among several types of disinhibitory problems that are often comorbid with alcohol dependence (AD). Lifetime problems with alcohol, marijuana, other drugs, childhood conduct disorder, and adult antisocial behavior were assessed in a sample of 426 young adults, 257 of whom had a lifetime diagnosis of AD. Higher delay discounting rates were associated with the covariation among all domains of disinhibitory problems and were not uniquely associated with any one domain. Higher delay discounting rates also were associated with lower intelligence, lower working memory capacity, and higher trait impulsivity. The results suggest that increased delay discounting of rewards may reflect aspects of a general vulnerability to externalizing, disinhibitory disorders.

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.

Familial Confounding of the Association Between Maternal Smoking During Pregnancy and Offspring Substance Use and Problems

CONTEXT Previous epidemiological, animal, and human cognitive neuroscience research suggests that maternal smoking during pregnancy (SDP) causes increased risk of substance use/problems in offspring. OBJECTIVE To determine the extent to which the association between SDP and offspring substance use/problems depends on confounded familial background factors by using a quasi-experimental design. DESIGN We used 2 separate samples from the United States and Sweden. The analyses prospectively predicted multiple indices of substance use and problems while controlling for statistical covariates and comparing differentially exposed siblings to minimize confounding. SETTING Offspring of a representative sample of women in the United States (sample 1) and the total Swedish population born during the period from January 1, 1983, to December 31, 1995 (sample 2). PATIENTS OR OTHER PARTICIPANTS Adolescent offspring of the women in the National Longitudinal Survey of Youth 1979 (n = 6904) and all offspring born in Sweden during the 13-year period (n = 1,187,360). MAIN OUTCOME MEASURES Self-reported adolescent alcohol, cigarette, and marijuana use and early onset (before 14 years of age) of each substance (sample 1) and substance-related convictions and hospitalizations for an alcohol- or other drug-related problem (sample 2). RESULTS The same pattern emerged for each index of substance use/problems across the 2 samples. At the population level, maternal SDP predicted every measure of offspring substance use/problems in both samples, ranging from adolescent alcohol use (hazard ratio [HR](moderate), 1.32 [95% CI, 1.22-1.43]; HR(high), 1.33 [1.17-1.53]) to a narcotics-related conviction (HR(moderate), 2.23 [2.14-2.31]; HR(high), 2.97 [2.86-3.09]). When comparing differentially exposed siblings to minimize genetic and environmental confounds, however, the association between SDP and each measure of substance use/problems was minimal and not statistically significant. CONCLUSIONS The association between maternal SDP and offspring substance use/problems is likely due to familial background factors, not a causal influence, because siblings have similar rates of substance use and problems regardless of their specific exposure to SDP.

Reduced cognitive ability in alcohol dependence: examining the role of covarying externalizing psychopathology.

Reduced executive cognitive ability is associated with alcohol dependence (AD) and other comorbid externalizing disorders. Working memory capacity, short-term memory, conditional associative learning, and intelligence were assessed in a sample (N = 477) with variation in lifetime histories of externalizing problems (conduct disorder, adult antisocial behavior, substance problems); this included a subsample (n = 285) with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) diagnosis of AD. Individuals with both AD and a history of childhood conduct disorder (CCD) scored lower on cognitive measures compared to those with AD and no history of CCD. Structural equation models showed that reduced ability in all cognitive domains was predicted by a latent externalizing factor reflecting covariation among lifetime problems with alcohol, drugs, childhood conduct, and adult antisocial behavior and was not uniquely related to any one problem. Further, for those with AD, the externalizing factor was associated with reductions in all the domains of cognitive ability. The results suggest that the reduced executive cognitive ability observed in AD individuals is partly accounted for by a general latent externalizing factor rather than alcohol-related problems per se.

Externalizing Psychopathology and Behavioral Disinhibition: Working Memory Mediates Signal Discriminability and Reinforcement Moderates Response Bias in Approach-Avoidance Learning

Research has suggested that reduced working memory capacity plays a key role in disinhibited patterns of behavior associated with externalizing psychopathology. In this study, participants (N = 365) completed 2 versions of a go/no-go mixed-incentive learning task that differed in the relative frequency of monetary rewards and punishments for correct and incorrect active-approach responses, respectively. Using separate structural equation models for conventional (hit and false alarm rates) and signal detection theory (signal discriminability and response bias) performance indices, distinct roles for working memory capacity and changes in payoff structure were found. Specifically, results showed that (a) working memory capacity mediated the effects of externalizing psychopathology on false alarms and discriminability of go versus no-go signals; (b) these effects were not moderated by the relative frequency of monetary rewards and punishments; (c) the relative frequency of monetary rewards and punishments moderated the effects of externalizing psychopathology on hits and response bias for go versus no-go responses; and (d) these effects were not mediated by working memory capacity. The findings implicate distinct roles for reduced working memory capacity and poorly modulated active approach and passive avoidance in the link between externalizing psychopathology and behavioral disinhibition.

Efficient perceptual tuning of hearing aids with genetic algorithms

We describe a system for integrating a genetic algorithm (GA) with perceptual feedback to perform an efficient search in a perceptual space. The main system components are an efficient method for estimating perceptual rank order and genetic operators that take advantage of the types of parameters found in certain classes of audio processing systems. Preference judgments are used, resulting in a lightweight user interface. The application to subjectively fitting a portable hearing aid based solely on binary feedback is discussed. An experiment was conducted using eight normal and eight hearing impaired subjects. Three parameters were varied to control cancellation of acoustic feedback. The GA worked well for fitting this system, as indicated by both objective and subjective measures. In addition, users had greatly differing preferences for feedback cancellation parameters and these preferences did not change much when subjects were retested.

Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring

Importance Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding. Objective To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems. Design, Setting, and Participants This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations. Exposures Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations. Main Outcomes and Measures Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring. Results Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons. Conclusions and Relevance Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

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.