Sexually Dimorphic Control of Parenting Behavior by the Medial Amygdala.

Social behaviors, including behaviors directed toward young offspring, exhibit striking sex differences. Understanding how these sexually dimorphic behaviors are regulated at the level of circuits and transcriptomes will provide insights into neural mechanisms of sex-specific behaviors. Here, we uncover a sexually dimorphic role of the medial amygdala (MeA) in governing parental and infanticidal behaviors. Contrary to traditional views, activation of GABAergic neurons in the MeA promotes parental behavior in females, while activation of this population in males differentially promotes parental versus infanticidal behavior in an activity-level-dependent manner. Through single-cell transcriptomic analysis, we found that molecular sex differences in the MeA are specifically represented in GABAergic neurons. Collectively, these results establish crucial roles for the MeA as a key node in the neural circuitry underlying pup-directed behaviors and provide important insight into the connection between sex differences across transcriptomes, cells, and circuits in regulating sexually dimorphic behavior.

Imprinted genes and the manipulation of parenting in mammals.

Genomic imprinting refers to the parent-of-origin expression of genes, which originates from epigenetic events in the mammalian germ line. The evolution of imprinting may reflect a conflict over resource allocation early in life, with silencing of paternal genes in offspring soliciting increased maternal provision and silencing of maternal genes limiting demands on the mother. Parental caregiving has been identified as an area of potential conflict, with several imprinted genes serendipitously found to directly influence the quality of maternal care. Recent systems biology approaches, based on single-cell RNA sequencing data, support a more deliberate relationship, which is reinforced by the finding that imprinted genes expressed in the offspring influence the quality of maternal caregiving. These bidirectional, reiterative relationships between parents and their offspring are critical both for short-term survival and for lifelong wellbeing, with clear implications for human health.

The parenting hub of the hypothalamus is a focus of imprinted gene action.

Imprinted genes are subject to germline epigenetic modification resulting in parental-specific allelic silencing. Although genomic imprinting is thought to be important for maternal behaviour, this idea is based on serendipitous findings from a small number of imprinted genes. Here, we undertook an unbiased systems biology approach, taking advantage of the recent delineation of specific neuronal populations responsible for controlling parental care, to test whether imprinted genes significantly converge to regulate parenting behaviour. Using single-cell RNA sequencing datasets, we identified a specific enrichment of imprinted gene expression in a recognised "parenting hub", the galanin-expressing neurons of the preoptic area. We tested the validity of linking enriched expression in these neurons to function by focusing on MAGE family member L2 (Magel2), an imprinted gene not previously linked to parenting behaviour. We confirmed expression of Magel2 in the preoptic area galanin expressing neurons. We then examined the parenting behaviour of Magel2-null(+/p) mice. Magel2-null mothers, fathers and virgin females demonstrated deficits in pup retrieval, nest building and pup-directed motivation, identifying a central role for this gene in parenting. Finally, we show that Magel2-null mothers and fathers have a significant reduction in POA galanin expressing cells, which in turn contributes to a reduced c-Fos response in the POA upon exposure to pups. Our findings identify a novel imprinted gene that impacts parenting behaviour and, moreover, demonstrates the utility of using single-cell RNA sequencing data to predict gene function from expression and in doing so here, have identified a purposeful role for genomic imprinting in mediating parental behaviour.

Testosterone's role in modulating human behaviors relevant to mating and parenting.

Testosterone (T) is linked to human mating and parenting. Here, we comprehensively reviewed evidence on whether, in men and women, (1) basal T levels are related to mating and parenting behaviors, (2) T responds to reproduction-relevant cues, (3) acute changes in T map onto subsequent mating and parenting behaviors, and (4) single-dose exogenous T administration causally affects mating and parenting behaviors. We examined whether the available evidence supports trade-off interpretations of T's adaptive function whereby high T levels correspond to greater mating/reproductive effort and competition and low T levels to greater parenting effort and nurturance. We found mixed support for trade-off hypotheses, suggesting that T's function in modulating human mating and parenting might be more nuanced and highly dependent on context and individual trait differences. Results were largely similar for men and women, although studies with women were scarcer than those with men for most behaviors we reviewed.

Parenting links to parent-child interbrain synchrony: a real-time fNIRS hyperscanning study.

Parent-child interaction is crucial for children's cognitive and affective development. While bio-synchrony models propose that parenting influences interbrain synchrony during interpersonal interaction, the brain-to-brain mechanisms underlying real-time parent-child interactions remain largely understudied. Using functional near-infrared spectroscopy, we investigated interbrain synchrony in 88 parent-child dyads (Mage children = 8.07, 42.0% girls) during a collaborative task (the Etch-a-Sketch, a joint drawing task). Our findings revealed increased interbrain synchrony in the dorsolateral prefrontal cortex and temporo-parietal areas during interactive, collaborative sessions compared to non-interactive, resting sessions. Linear regression analysis demonstrated that interbrain synchrony in the left temporoparietal junction was associated with enhanced dyadic collaboration, shared positive affect, parental autonomy support, and parental emotional warmth. These associations remained significant after controlling for demographic variables including child age, child gender, and parent gender. Additionally, differences between fathers and mothers were observed. These results highlight the significant association between brain-to-brain synchrony in parent-child dyads, the quality of the parent-child relationship, and supportive parenting behaviors. Interbrain synchrony may serve as a neurobiological marker of real-time parent-child interaction, potentially underscoring the pivotal role of supportive parenting in shaping these interbrain synchrony mechanisms.

Cortical volume reductions in men transitioning to first-time fatherhood reflect both parenting engagement and mental health risk.

Perinatal reductions in gray matter volume have been observed in human mothers transitioning to parenthood, with preliminary evidence for similar changes in fathers. These reductions have been theorized to support adaptation to parenting, but greater investigation is needed. We scanned 38 first-time fathers during their partner's pregnancy and again after 6 months postpartum, and collected self-report data prenatally and 3, 6, and 12 months postpartum. Significant gray matter volume reductions were observed across the entire cortex but not the subcortex. Fathers who reported stronger prenatal bonding with the unborn infant, and planned to take more time off from work after birth, subsequently showed larger cortical volume decreases. Larger reductions in gray matter volume also emerged among fathers who reported stronger postpartum bonding with the infant, lower parenting stress, and more time spent with their infant. Larger volume reductions predicted more postpartum sleep problems and higher levels of postpartum depression, anxiety, and psychological distress, controlling for prenatal sleep and mental health. Volume reductions were smaller among fathers whose infants were older at the postpartum scan, indicating potential rebound. These results suggest that perinatal gray matter volume reductions might reflect not only greater parenting engagement but also increased mental health risk in new fathers.

Evidence for an adolescent sensitive period to family experiences influencing adult male testosterone production.

Across vertebrates, testosterone is an important mediator of reproductive trade-offs, shaping how energy and time are devoted to parenting versus mating/competition. Based on early environments, organisms often calibrate adult hormone production to adjust reproductive strategies. For example, favorable early nutrition predicts higher adult male testosterone in humans, and animal models show that developmental social environments can affect adult testosterone. In humans, fathers' testosterone often declines with caregiving, yet these patterns vary within and across populations. This may partially trace to early social environments, including caregiving styles and family relationships, which could have formative effects on testosterone production and parenting behaviors. Using data from a multidecade study in the Philippines (n = 966), we tested whether sons' developmental experiences with their fathers predicted their adult testosterone profiles, including after they became fathers themselves. Sons had lower testosterone as parents if their own fathers lived with them and were involved in childcare during adolescence. We also found a contributing role for adolescent father­son relationships: sons had lower waking testosterone, before and after becoming fathers, if they credited their own fathers with their upbringing and resided with them as adolescents. These findings were not accounted for by the sons' own parenting and partnering behaviors, which could influence their testosterone. These effects were limited to adolescence: sons' infancy or childhood experiences did not predict their testosterone as fathers. Our findings link adolescent family experiences to adult testosterone, pointing to a potential pathway related to the intergenerational transmission of biological and behavioral components of reproductive strategies.

Evolutionary trade-offs between testes size and parenting in Neotropical glassfrogs.

In males, large testes size signifies high sperm production and is commonly linked to heightened sperm competition levels. It may also evolve as a response to an elevated risk of sperm depletion due to multiple mating or large clutch sizes. Conversely, weapons, mate or clutch guarding may allow individuals to monopolize mating events and preclude sperm competition, thereby reducing the selection of large testes. Herein, we examined how paternal care, sexual size dimorphism (SSD), weaponry and female fecundity are linked to testes size in glassfrogs. We found that paternal care was associated with a reduction in relative testes size, suggesting an evolutionary trade-off between testes size and parenting. Although females were slightly larger than males and species with paternal care tended to have larger clutches, there was no significant relationship between SSD, clutch size and relative testes size. These findings suggest that the evolution of testes size in glassfrogs is influenced by sperm competition risk, rather than sperm depletion risk. We infer that clutch guarding precludes the risk of fertilization by other males and consequently diminishes selective pressure for larger testes. Our study highlights the prominent role of paternal care in the evolution of testes size in species with external fertilization.

Executive Function in Preschool Children with Congenital Heart Disease and Controls: The Role of a Cognitively Stimulating Home Environment.

OBJECTIVE: To assess the relationships between (1) environmental and demographic factors and executive function (EF) in preschool children with congenital heart disease (CHD) and controls and (2) clinical and surgical risk factors and EF in preschool children with CHD. STUDY DESIGN: At 4-6 years of age, parents of children with CHD (n = 51) and controls (n = 124) completed the Behavior Rating Inventory of Executive Function, Preschool Version questionnaire and the Cognitively Stimulating Parenting Scale (CSPS). Multivariable general linear modeling assessed the relationship between Behavior Rating Inventory of Executive Function, Preschool Version composite scores (Inhibitory Self-Control Index [ISCI], Flexibility Index [FI], and Emergent Metacognition Index [EMI]) and group (CHD/control), sex, age at assessment, gestational age, Index of Multiple Deprivation, and CSPS scores. The relationships between CHD type, surgical factors, and brain magnetic resonance imaging injury rating and ISCI, FI, and EMI scores were assessed. RESULTS: The presence of CHD, age at assessment, sex, and Index of Multiple Deprivation were not associated with EF scores. Lower gestational age was associated with greater ISCI and FI scores, and age at assessment was associated with lower FI scores. Group significantly moderated the relationship between CSPS and EF, such that CSPS significantly predicted EF in children with CHD (ISCI: P = .0004; FI: P = .0015; EMI: P = .0004) but not controls (ISCI: P = .2727; FI: P = .6185; EMI: P = .3332). There were no significant relationships between EF scores and surgical factors, CHD type, or brain magnetic resonance imaging injury rating. CONCLUSIONS: Supporting parents to provide a cognitively stimulating home environment may improve EF in children with CHD. The home and parenting environment should be considered when designing intervention studies aimed at improving EF in this patient group.

Reported Intergenerational Transmission of Parent Weight Talk and Links with Child Health and Wellbeing.

OBJECTIVES: To examine if intergenerational transmission of parent weight talk occurs, the contextual factors prompting weight talk, and whether parent weight talk is associated with child weight, dietary intake, psychosocial outcomes, and food parenting practices. STUDY DESIGN: Children aged 5-9 years and their families (n = 1307) from 6 racial and ethnic groups (African-American, Hispanic, Hmong, Native American, Somali/Ethiopian, White) were recruited for a longitudinal cohort study through primary care clinics in Minneapolis/St. Paul, Minnesota from 2016 through 2019. Parents filled out surveys at 2 time points, 18 months apart. Adjusted regression models examined associations of interest. RESULTS: Intergenerational transmission of parent weight talk was observed. In addition, significant associations were found between parent engagement in weight talk and higher weight status and poorer psychosocial outcomes in children 18 months later. Parent engagement in weight talk was also associated with more restrictive food parenting practices 18 months later. CONCLUSIONS: Parents' exposure to weight talk as children increased the likelihood of engaging in weight talk with their own children and had harmful associations over time with parent restrictive feeding practices, child weight, and psychosocial wellbeing in children. Health care providers may want to consider both modeling positive health-focused conversations and educating parents about the potential harmful and long-lasting consequences of engaging in weight talk with their children.

The Combined Contributions of Newborn Stress and Parenting Stress on Toddler Language Development.

OBJECTIVE: To examine the longitudinal associations between newborn neurobehavioral stress signs, maternal parenting stress, and several indices of toddler language development. STUDY DESIGN: Participants include 202 mother-infant dyads (104 girls). We measured stress signs in neonates in the hospital at least 24 hours after birth using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. At 7 months, parenting stress (competence, attachment, and role restriction) was assessed using the Parenting Stress Index. At 18 months, mothers completed the Communicative Development Inventories, which measured toddler gesturing, expressive vocabulary, and receptive vocabulary. Longitudinal path modeling was used to estimate associations between neonatal stress signs, parenting stress, and toddler language, and a model was generated for each language outcome. Child sex, birth weight, and family income were included as covariates. RESULTS: Infants who exhibited greater neurobehavioral stress signs at birth produced significantly fewer social-communicative gestures at 18 months of age. Among infants whose mothers reported low (but not high) levels of parenting stress during the first postnatal year, newborn stress signs were negatively associated with 18-month-olds' receptive vocabulary size. Neither newborn stress signs nor parenting stress were significantly related to toddler expressive vocabulary size. CONCLUSIONS: Our findings uncover a negative association between newborn stress signs and toddler gesturing. Furthermore, our results suggest that caregiver stress and neonatal stress signs interact to predict toddler receptive vocabulary. Taken together, these results demonstrate that some neonates who exhibit increased neurobehavioral stress signs may be at heightened risk for experiencing language difficulties. These children may benefit from additional support in infancy.

Intergenerational transmission of ADHD behaviors: genetic and environmental pathways.

BACKGROUND: We investigate if covariation between parental and child attention-deficit hyperactivity disorder (ADHD) behaviors can be explained by environmental and/or genetic transmission. METHODS: We employed a large children-of-twins-and-siblings sample (N = 22 276 parents and 11 566 8-year-old children) of the Norwegian Mother, Father and Child Cohort Study. This enabled us to disentangle intergenerational influences via parental genes and parental behaviors (i.e. genetic and environmental transmission, respectively). Fathers reported on their own symptoms and mothers on their own and their child's symptoms. RESULTS: Child ADHD behaviors correlated with their mother's (0.24) and father's (0.10) ADHD behaviors. These correlations were largely due to additive genetic transmission. Variation in children's ADHD behaviors was explained by genetic factors active in both generations (11%) and genetic factors specific to the children (46%), giving a total heritability of 57%. There were small effects of parental ADHD behaviors (2% environmental transmission) and gene-environment correlation (3%). The remaining variability in ADHD behaviors was due to individual-specific environmental factors. CONCLUSIONS: The intergenerational resemblance of ADHD behaviors is primarily due to genetic transmission, with little evidence for parental ADHD behaviors causing children's ADHD behaviors. This contradicts theories proposing environmental explanations of intergenerational transmission of ADHD, such as parenting theories or psychological life-history theory.

Offspring overcome poor parenting by being better parents.

The evolutionary repercussions of parental effects-the impact of the developmental environment provided by parents on offspring-are often discussed as static effects that can have negative influences on offspring fitness that may even persist across generations. However, individuals are not passive recipients and may mitigate the persistence of parental effects through their behaviour. Here, we tested how the burying beetle, Nicrophorus orbicollis, a species with complex parental care, responded to poor parenting. We cross-fostered young and manipulated the duration of parental care received and measured the impact on traits of both F1 and F2 offspring to experimentally extricate the effect of poor parenting from other parental effects. As expected, reducing parental care negatively affected traits that are ecologically important for burying beetles, including F1 offspring development time and body size. However, F1 parents that received reduced care as larvae spent more time feeding F2 offspring than parents that received full care as larvae. As a result, both the number and mass of F2 offspring were unaffected by the developmental experience of their parents. Our results show that flexible parental care may be able to overcome poor developmental environments and limit negative parental effects to a single generation.

Observed collaborative and intrusive parenting behaviours associated with psychosocial outcomes of adolescents with type 1 diabetes and their maternal caregivers.

AIMS: Maternal caregiver involvement is strongly associated with psychosocial and glycemic outcomes amongst adolescents with type 1 diabetes (T1D); however, previous studies have lacked detailed, objective examinations of caregiver involvement. We examined the relationship between observed parenting behaviors and psychosocial and glycemic outcomes amongst youth with T1D. METHODS: Data collected from adolescents with T1D (age 11-17) and their female caregivers as a part of a randomized controlled trial were analyzed. These included structured, observation-based scores of adolescent-caregiver dyads engaged in videotaped interactions and selected psychosocial and glycemic outcome measures. RESULTS: In adjusted analyses, higher levels of intrusive parenting behaviors during observed interactions were associated with higher diabetes distress in adolescents, but no difference in HbA1c. Associations between intrusive parenting behaviors and psychosocial outcomes were stronger for females compared to males for both diabetes distress and quality of life. Similarly, associations between collaborative parenting behaviors and quality of life were stronger for female adolescents than males. No associations were observed between collaborative parenting behaviors and glycemic outcomes. Consistent with previous work, we noted higher levels of adolescent-reported family conflict were associated with lower adolescent quality of life and higher diabetes distress with no significant difference between male and female adolescents. CONCLUSION: These findings indicate that high levels of intrusive parenting behaviors, such as lecturing or over-controlling behaviors, are associated with lower levels of adolescent well-being, particularly among adolescent girls. This work suggests that interventions to reduce intrusive parenting by maternal caregivers could result in improved psychosocial outcomes for adolescents with T1D.

Parental Nurturance Moderates the Etiology of Youth Resilience.

Parenting behaviors are among the most robust predictors of youth resilience to adversity. Critically, however, very few studies examining these effects have been genetically-informed, and none have considered parenting as an etiologic moderator of resilience. What's more, despite the multidimensionality of resilience, extant etiologic literature has largely focused on a single domain. The current study sought to fill these respective gaps in the literature by examining whether and how parental nurturance shapes the etiology of academic, social, and psychological resilience, respectively. We employed a unique sample of twins (N = 426 pairs; ages 6-11) exposed to moderate-to-severe levels of environmental adversity (i.e., family poverty, neighborhood poverty, community violence) from the Twin Study of Behavioral and Emotional Development in Children. As expected, parental nurturance was positively correlated with all forms of resilience. Extended univariate genotype-by-environment interaction models revealed that parental nurturance significantly moderated genetic influences on all three domains of resilience (academic resilience A1= -0.53, psychological resilience A1= -1.22, social resilience A1= -0.63; all p < .05), such that as parental nurturance increased, genetic influences on youth resilience decreased. Put another way, children experiencing high levels of parental nurturance were more resilient to disadvantage, regardless of their genetic predisposition towards resilience. In the absence of nurturing parenting, however, genetic influences played an outsized role in the origins of resilience. Such findings indicate that parental nurturance may serve as a malleable protective factor that increases youth resilience regardless of genetic influences.

Alcohol Use Disorder Polygenic Risk Scores and Trajectories of Early Adolescent Externalizing Behaviors: Examining the Role of Parenting and Family Conflict in the Racially/Ethnically Diverse ABCD Sample.

This study examined the independent and interactive effects of alcohol use disorder genome-wide polygenic scores (AUD-PGS) and parenting and family conflict on early adolescent externalizing behaviors. Data were drawn from White (N = 6181, 46.9% female), Black/African American (N = 1784, 50.1% female), and Hispanic/Latinx (N = 2410, 48.0% female) youth from the adolescent brain cognitive development Study (ABCD). Parents reported on youth externalizing behaviors at baseline (T1, age 9/10), 1-year (T2, age 10/11) and 2-year (T3, age 11/12) assessments. Youth reported on parenting and family environment at T1 and provided saliva or blood samples for genotyping. Results from latent growth models indicated that in general externalizing behaviors decreased from T1 to T3. Across all groups, higher family conflict was associated with more externalizing behaviors at T1, and we did not find significant associations between parental monitoring and early adolescent externalizing behaviors. Parental acceptance was associated with lower externalizing behaviors among White and Hispanic youth, but not among Black youth. Results indicated no significant main effect of AUD-PGS nor interaction effect between AUD-PGS and family variables on early adolescent externalizing behaviors. Post hoc exploratory analysis uncovered an interaction between AUD-PGS and parental acceptance such that AUD-PGS was positively associated with externalizing rule-breaking behaviors among Hispanic youth, but only when parental acceptance was very low. Findings highlight the important role of family conflict and parental acceptance in externalizing behaviors among early adolescents, and emphasize the need to examine other developmental pathways underlying genetic risk for AUD across diverse populations.

Interactions Between Genetic, Prenatal Substance Use, Puberty, and Parenting are Less Important for Understanding Adolescents' Internalizing, Externalizing, and Substance Use than Developmental Cascades in Multifactorial Models.

This study tested interactions among puberty-related genetic risk, prenatal substance use, harsh discipline, and pubertal timing for the severity and directionality (i.e., differentiation) of externalizing and internalizing problems and adolescent substance use. This is a companion paper to Marceau et al. (2021) which examined the same influences in developmental cascade models. Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (n = 4504 White boys, n = 4287 White girls assessed from the prenatal period through 18.5 years). We hypothesized generally that later predictors would strengthen the influence of puberty-related genetic risk, prenatal substance use exposure, and pubertal risk on psychopathology and substance use (two-way interactions), and that later predictors would strengthen the interactions of earlier influences on psychopathology and substance use (three-way interactions). Interactions were sparse. Although all fourteen interactions showed that later influences can exacerbate or trigger the effects of earlier ones, they often were not in the expected direction. The most robust moderator was parental discipline, and differing and synergistic effects of biological and socially-relevant aspects of puberty were found. In all, the influences examined here operate more robustly in developmental cascades than in interaction with each other for the development of psychopathology and transitions to substance use.

Rebuild the Academy: Supporting academic mothers during COVID-19 and beyond.

The issues facing academic mothers have been discussed for decades. Coronavirus Disease 2019 (COVID-19) is further exposing these inequalities as womxn scientists who are parenting while also engaging in a combination of academic related duties are falling behind. These inequities can be solved by investing strategically in solutions. Here we describe strategies that would ensure a more equitable academy for working mothers now and in the future. While the data are clear that mothers are being disproportionately impacted by COVID-19, many groups could benefit from these strategies. Rather than rebuilding what we once knew, let us be the architects of a new world.

Paternal involvement in infant care and developmental milestone outcomes at age 3 years: the Japan Environment and Children's Study (JECS).

BACKGROUND: In developed countries, the time fathers spend on childcare has increased steadily in recent decades. However, studies on the relationship between paternal care and child outcomes remain scarce. Thus, we examined the association between paternal involvement in childcare and children's developmental outcomes. METHODS: We used Japan's largest birth cohort data, the Japan Environment and Children's Study, to examine the relationship between paternal involvement in childcare at the child's age of 6 months and developmental milestone outcomes at the child's age of 3 years (n = 28,050). Developmental delays were assessed with Ages and Stages Questionnaire. Potential mediation by maternal parenting stress at the child's age of 1.5 years was also examined. We used log-binomial regression analyses to estimate risk ratios. RESULTS: Fathers' high involvement in childcare was associated with a lower risk of developmental delay in gross-motor, fine-motor, problem solving, and personal-social domains compared with low involvement, adjusting for potential confounders. For example, the risk ratio with 95% confidence intervals was 0.76 [0.67, 0.86] for the gross-motor domain. We also observed that the associations were partially mediated by maternal parenting stress. CONCLUSIONS: Fathers' active involvement in childcare during infancy may promote young children's development, partially by reducing maternal parenting stress. IMPACT: Using Japan's largest birth cohort data (Japan Environment and Children's Study), we showed that paternal involvement in infant care might benefit young children's development. Fathers' active involvement in infant care was associated with a lower risk of developmental delays in gross-motor, fine-motor, problem solving, and personal-social domains. Maternal parenting stress may mediate the association between paternal involvement in infant care and child development outcomes at 3 years.

Developmental trajectories of late preterm infants and predictors of academic performance.

BACKGROUND: The trajectories of late preterm development from infancy to kindergarten reading and math, and predictors of academic resilience and risk are unknown. METHODS: Sample included 1200 late preterm infants (LPIs) from the Early Childhood Longitudinal Study, Birth Cohort. Objective measurements of development at 9 and 24 months (Bayley-SFR) and reading and math academic achievement at preschool and kindergarten were standardized; trajectories of late preterm development from 9 months to kindergarten reading and math were identified using latent class growth analysis. Multinomial logistic regression [aOR, 95% CI] identified predictors of academic resilience and risk. RESULTS: Four trajectory groups were observed for reading and three for math. More optimal trajectories (in reading and math) and academic resilience were associated with experiencing sensitive parenting and preschool attendance. Suboptimal (at-risk) trajectories (in reading or math) and an increased odds of academic risk were associated with