Offspring Outcomes Research Articles

Untangling risky discourse with evidence: A scoping review of outcomes for teen mothers’ offspring

Concerns for the long-term health and social well-being of teen mothers and their children arose in the 1970s as early childbearing was depicted as a public health problem. Early researchers identified the high-risk nature of teen mothering and a host of unfavorable maternal-child outcomes. The purpose of this study is to review the research published since 2010 on the outcomes for teen mothers’ offspring ≥ 6 years of age; to examine trends in the types of studies conducted; and to identify the strengths and limitations of this research. MethodWe conducted a systematic search of 8 databases to identify studies that examined outcomes for offspring ≥ 6 years from high-income countries. We grouped studies by offspring age (child ≥ 6 years of age, adolescents, and adults) and outcomes in the domains of mental health, physical health, education, sexual activity, delinquency/crime, and substance use. Child outcomes were examined in 16 studies, adolescent outcomes in 31, and adult outcomes in 14. FindingsOf the 53 studies published between 2010 to November 2022, 32 originated in the U.S.; 9 in Sweden; 2 each in Canada and Taiwan; and 8 elsewhere. Since 2010, researchers have increasingly used national samples and sibling and cousin comparisons to control for selection into teen mothering. These studies have reduced, and in some cases, eliminated young maternal age as a predictor, suggesting that poor outcomes are largely due to factors related to teen mothers’ preexisting disadvantage. ConclusionsThe results of this scoping review echo a chorus of scholars who have long argued that the poor outcomes attributed to teen mothering disregard the systemic inequities that predispose youth to become teen parents. Because these upstream conditions are baked into the social worlds that most teen mothers and their children inherit, delaying childbearing in the absence of mitigating these conditions is unlikely to improve maternal-child outcomes. We urge researchers to adjust for selection into teen mothering; examine heterogeneity in samples; adjust for birth year when multiple birth cohorts are combined in a study; place findings in historical context; consider variables that align with the perspectives of teen mothers; and study the intergenerational effects of adverse childhood experiences. Doing so would improve our understanding not only of causal relationships but the context and temporality of maternal-child outcomes.

Influence of substance use on male reproductive health and offspring outcomes.

The prevalence of substance use globally is rising and is highest among men of reproductive age. In Africa, and South and Central America, cannabis use disorder is most prevalent and in Eastern and South-Eastern Europe, Central America, Canada and the USA, opioid use disorder predominates. Substance use might be contributing to the ongoing global decline in male fertility, and emerging evidence has linked paternal substance use with short-term and long-term adverse effects on offspring development and outcomes. This trend is concerning given that substance use is increasing, including during the COVID-19 pandemic. Preclinical studies have shown that male preconception substance use can influence offspring brain development and neurobehaviour through epigenetic mechanisms. Additionally, human studies investigating paternal health behaviours during the prenatal period suggest that paternal tobacco, opioid, cannabis and alcohol use is associated with reduced offspring mental health, in particular hyperactivity and attention-deficit hyperactivity disorder. The potential effects of paternal substance use are areas in which to focus public health efforts and health-care provider counselling of couples or individuals interested in conceiving.

Amino Acids during Pregnancy and Offspring Cardiovascular-Kidney-Metabolic Health.

Amino acids are essential for normal pregnancy and fetal development. Disruptions in maternal amino acid metabolism have been associated with various adult diseases later in life, a phenomenon referred to as the developmental origins of health and disease (DOHaD). In this review, we examine the recent evidence highlighting the significant impact of amino acids on fetal programming, their influence on the modulation of gut microbiota, and their repercussions on offspring outcomes, particularly in the context of cardiovascular-kidney-metabolic (CKM) syndrome. Furthermore, we delve into experimental studies that have unveiled the protective effects of therapies targeting amino acids. These interventions have demonstrated the potential to reprogram traits associated with CKM in offspring. The discussion encompasses the challenges of translating the findings from animal studies to clinical applications, emphasizing the complexity of this process. Additionally, we propose potential solutions to overcome these challenges. Ultimately, as we move forward, future research endeavors should aim to pinpoint the most effective amino-acid-targeted therapies, determining the optimal dosage and mode of administration. This exploration is essential for maximizing the reprogramming effects, ultimately contributing to the enhancement of cardiovascular-kidney-metabolic health in offspring.

Long-term neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy: a multicentre cohort study of the International Network on Cancer, Infertility, and Pregnancy

The main data available on the safety of radiation during pregnancy originate from animal studies and from studies of survivors of atomic or nuclear disasters. The effect of radiotherapy to treat maternal cancer on fetal development is uncertain. This report presents a unique cohort and aims to determine the long-term neurocognitive, psychosocial and physical outcomes of offspring of mothers treated with radiotherapy during pregnancy. In this international, multicentre, mixed retrospective-prospective cohort study, we recruited participants between Aug 5, 2006, and Aug 24, 2023, aged between 1·5 and 46 years, at three referral centres in Belgium, the Netherlands, and the USA. Participants were eligible if they were born from mothers treated with radiotherapy during pregnancy. Fetal radiation doses were obtained from medical records and participants were followed up at predefined ages (1·5, 3, 6, 9, 12, 15, and 18 years) and 5-yearly in adulthood, based on age at enrolment, using a neurocognitive test battery (measuring intelligence, attention, and memory), parent-reported executive function and psychosocial questionnaires, and a medical assessment. Results were compared with test-specific normative data. Linear regression models investigated associations between radiotherapy factors (fetal radiation dose, gestational age at the start and end of radiotherapy, and radiotherapy duration) and outcomes. 68 maternal cases of radiotherapy during pregnancy were registered by the three participating centres, of which 61 resulted in a livebirth and were therefore eligible to participate in the child follow-up study. After excluding those who did not give consent, 43 participants born from 42 mothers treated with radiotherapy during pregnancy were included in the study (median age at first assessment 3 years [IQR 2-11]; median age at last assessment 12 years [9-18]; median number of assessments two [1-4]). 18 (42%) of the included participants were female and 25 (58%) male, and 37 (86%) were of White ethnicity. Mean neurocognitive outcomes of the entire cohort were within normal ranges. No associations were found with fetal radiation dose or timing of radiotherapy during pregnancy. Six (16%) of 38 participants with neurocognitive outcomes scored lower than one SD on at least one neurocognitive outcome, three (7%) reported chronic medical conditions (spasmophilia, spastic diplegia, and IgG deficiency), and three (7%) were diagnosed with attention-deficit hyperactivity disorder (of whom two scored lower on attention). Of ten (23%) participants with lower neurocognitive score(s), a chronic medical condition, or attention-deficit hyperactivity disorder, eight were born preterm. The remaining 33 (77%) participants showed no neurocognitive, psychosocial, or chronic physical problems. We show on average normal neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy. Differences in outcomes could not be explained by exposure to radiotherapy during pregnancy. These results suggest that extra-abdomino-pelvic radiotherapy exposure during pregnancy in general does not adversely affect outcomes of liveborn children. Further research with a larger sample is necessary to confirm these findings. Kom Op Tegen Kanker, KWF Kankerbestrijding, Stichting Tegen Kanker, Research Foundation Flanders.

Characteristics of women concordant and discordant for urine drug screens for cannabis exposure and self-reported cannabis use during pregnancy

BackgroundIncreasing cannabis use among pregnant people and equivocal evidence linking prenatal cannabis exposure to adverse outcomes in offspring highlights the need to understand its potential impact on pregnancy and child outcomes. Assessing cannabis use during pregnancy remains a major challenge with potential influences of stigma on self-report as well as detection limitations of easily collected biological matrices. ObjectiveThis descriptive study examined the concordance between self-reported (SR) cannabis use and urine drug screen (UDS) detection of cannabis exposure during the first trimester of pregnancy and characterized concordant and discordant groups for sociodemographic factors, modes of use, secondhand exposure to cannabis and tobacco, and alcohol use and cotinine positivity. Study designThe Cannabis Use During Development and Early Life (CUDDEL) Study is an ongoing longitudinal study that recruits pregnant individuals presenting for obstetric care, who report lifetime cannabis use as well as using (n = 289) or not using cannabis (n = 169) during pregnancy. During the first trimester pregnancy visit, SR of cannabis use and a UDS for cannabis, other illicit drugs and nicotine are acquired from eligible participants, of whom 333 as of 05/01/2023 had both. ResultsUsing available CUDDEL Study data on both SR and UDS (n = 333; age 26.6 ± 4.7; 88.6% Black; 45.4% below federal poverty threshold; 56.5% with paid employment; 89% with high school education; 22% first pregnancy; 12.3 ± 3.6 weeks gestation), we classified pregnant individuals with SR and UDS data into 4 groups based on concordance (k = 0.49 [95% C.I. 0.40–0.58]) between SR cannabis use and UDS cannabis detection during the first trimester: 1) SR+/UDS+ (n = 107); 2) SR-/UDS- (n = 142); 3) SR+/UDS- (n = 44); 4) SR-/UDS+ (n = 40). Those who were SR+/UDS- reported less frequent cannabis use and fewer hours under the influence of cannabis during their pregnancy. Those who were SR-/UDS+ were more likely to have joined the study at a lower gestational age with 62.5% reporting cannabis use during their pregnancy prior to being aware that they were pregnant. Of the 40 SR-/UDS+ women, 14 (i.e., 35%) reported past month secondhand exposure, or blunt usage. In the subset of individuals with SR and UDS available at trimester 2 (N = 160) and 3 (N = 140), concordant groups were mostly stable and > 50% of those in the discordant groups became concordant by the second trimester. Classifying individuals as exposed or not exposed who were SR+ and/or UDS+ resulted in minor changes in group status based on self-report at screening. ConclusionOverall, there was moderate concordance between SR and UDS for cannabis use/exposure during pregnancy. Instances of SR+/UDS- discordancy may partially be attributable to lower levels of use that are not detected on UDS. SR-/UDS+ discordancy may arise from recent use prior to knowledge of pregnancy, extreme secondhand exposure, deception, and challenges with completing questionnaires. Acquiring both self-report and biological detection of cannabis use/exposure allows for the examination of convergent evidence. Classifying those who are SR+ and/or UDS+ as individuals who used cannabis during their first trimester after being aware of their pregnancy resulted in only a minor change in exposure status; thus, relying on self-report screening, at least in this population and within this sociocultural context likely provides an adequate approximation of cannabis use during pregnancy.

Low dose aspirin prevents endothelial dysfunction in the aorta and foetal loss in pregnant mice infected with influenza A virus.

Influenza A virus (IAV) infection in pregnancy resembles a preeclamptic phenotype characterised by vascular dysfunction and foetal growth retardation. Given that low dose aspirin (ASA) is safe in pregnancy and is used to prevent preeclampsia, we investigated whether ASA or NO-conjugated aspirin, NCX4016, resolve vascular inflammation and function to improve offspring outcomes following IAV infection in pregnant mice. Pregnant mice were intranasally infected with a mouse adapted IAV strain (Hkx31; 104 plaque forming units) and received daily treatments with either 200µg/kg ASA or NCX4016 via oral gavage. Mice were then culled and the maternal lungs and aortas collected for qPCR analysis, and wire myography was performed on aortic rings to assess endothelial and vascular smooth muscle functionality. Pup and placentas were weighed and pup growth rates and survival assessed. IAV infected mice had an impaired endothelial dependent relaxation response to ACh in the aorta, which was prevented by ASA and NCX4016 treatment. ASA and NCX4016 treatment prevented IAV dissemination and inflammation of the aorta as well as improving the pup placental ratios in utero, survival and growth rates at post-natal day 5. Low dose ASA is safe to use during pregnancy for preeclampsia and this study demonstrates that ASA may prove a promising treatment for averting the significant vascular complications associated with influenza infection during pregnancy.

Associations between psychiatric diagnoses in parents and psychiatric, behavioral, psychosocial outcomes in their offspring: a Swedish population-based register study

IntroductionChildren with parents with psychiatric diagnoses have an increased probability for not only the same condition as their parent, but also for other conditions and behavioral and psychosocial problems. Whereas many studies have focused on parental severe mental illness due to their significant impairment, less attention has been paid to more common disorders despite their higher prevalence. In addition, because most past research only included one exposure or one outcome at a time, it remains difficult to examine and compare broad patterns of intergenerational transmission.ObjectivesTo examine associations between six parental psychiatric diagnoses in parents, and a broad range of psychiatric diagnoses, psychotropic medications, criminality, suicide, violent victimization, accidents, and school and labor performance in their offspring.MethodsBased on Swedish national registers, we linked all individuals born in Sweden between 1970 and 2000 to their biological parents (N = 3 286 293). We used a matched cohort design, analyzed with stratified Cox regression and conditional logistic regressions to examine associations between six psychiatric diagnoses in the parents, and 32 outcomes in their offspring. All exposed and unexposed children were followed from their date of birth to the date of emigration from Sweden, the death, or 31 December 2013 when the offspring were 14-44 years old.ResultsIn terms of absolute risk, most children who had parents with psychiatric diagnoses were not diagnosed in specialist care themselves, as the proportion of having any of the 16 types of psychiatric conditions ranged from 22.17% (exposed to parental depression) to 25.05% (exposed to parental drug-related disorders) at the end of follow-up. Nevertheless, in terms of relative risk, all six parental psychiatric diagnoses increased the probability of all 32 outcomes in their offspring, with the Hazard Ratio ranging from 1.04 to 8.91 for time-to-event outcomes, and the Odds Ratio ranging from 1.29 to 3.36 for binary outcomes. Some specificities were observed for parental psychotic and substance misuse diagnoses, which strongly predicted offspring psychotic-like and externalizing-related outcomes, respectively.ConclusionsThe intergenerational transmission of parental psychiatric conditions appeared largely transdiagnostic, even for non-psychiatric outcomes in offspring. Given the broad spectrum of associations with the outcomes, service providers (e.g., psychiatrists, teachers, and social workers) should consider clients’ broader psychiatric family history when predicting prognosis and planning interventions/treatment.Disclosure of InterestNone Declared

A Systematic Review and Meta-analysis: Paternal Anxiety and the Emotional and Behavioral Outcomes in Their Offspring

Anxiety disorders are highly prevalent worldwide; however, the literature lacks a meta-analytic quantification of the risk posed by fathers' anxiety for offspring development. This systematic review and meta-analysis aimed to provide a comprehensive estimate of the magnitude of the association between paternal anxiety and emotional and behavioral problems of offspring. In February 2022, Web of Science, Ovid (Embase, MEDLINE, PsycINFO), Trip Database, and ProQuest were searched to identify all quantitative studies that measured anxiety in fathers and emotional and/or behavioral outcomes in offspring. No limits were set for offspring age, publication language, or publication year. Summary estimates were extracted from the primary studies. Meta-analytic random-effects 3-level models were used to calculate correlation coefficients. Quality was assessed using the Newcastle-Ottawa Scale. The study protocol was preregistered with PROSPERO (CRD42022311501) and adhered to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines. Of 11,746 records identified, 98 were included in the meta-analysis. Small but significant associations were found between paternal anxiety and offspring emotional and behavioral problems overall (r= 0.16, 95% CI [0.13, 0.19]) and behavioral (r= 0.19, 95% CI [0.13, 0.24]), emotional (r= 0.15, 95% CI [0.12, 0.18]), anxiety (r= 0.13, 95% CI [0.11, 0.16]), and depression (r= 0.13, 95% CI [0.03, 0.23]) problems. Some significant moderators were identified. Paternal mental health is associated with offspring development, and the offspring of fathers with anxiety symptoms or disorders are at increased risk of negative emotional and behavioral outcomes, in line with the principles of multifinality and pleiotropy. The substantial heterogeneity among studies and the overrepresentation of White European American groups in this literature highlight the need for further research. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list.

Maternal circadian rhythm disruption affects neonatal inflammation via metabolic reprograming of myeloid cells.

Disruption of circadian rhythm during pregnancy produces adverse health outcomes in offspring; however, the role of maternal circadian rhythms in the immune system of infants and their susceptibility to inflammation remains poorly understood. Here we show that disruption of circadian rhythms in pregnant mice profoundly aggravates the severity of neonatal inflammatory disorders in both male and female offspring, such as necrotizing enterocolitis and sepsis. The diminished maternal production of docosahexaenoic acid (DHA) and the impaired immunosuppressive function of neonatal myeloid-derived suppressor cells (MDSCs) contribute to this phenomenon. Mechanistically, DHA enhances the immunosuppressive function of MDSCs via PPARγ-mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieves neonatal inflammation induced by maternal rhythm disruption. These observations collectively demonstrate a previously unrecognized role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.

Associations between general and specific psychopathology factors in parents and psychiatric, behavioral, and psychosocial outcomes in offspring: a Swedish population-based register study

IntroductionPsychiatric conditions in parents are associated not only with the same condition in offspring, but also with virtually all other psychiatric conditions. However, it remains unknown whether this intergenerational transmission of psychiatric conditions was attributable to broader psychopathology comorbidity or to specific conditions.ObjectivesTo estimate associations between general and specific factors of psychopathology in parents, and a wide range of register-based outcomes in their offspring.MethodsBased on Swedish national registers, we linked 2 947 703 individuals born in Sweden between 1970 and 2000 to their biological parents (1 705 780 pairs of parents) and followed them to December 31, 2013. First, we estimated one general and three unrelated (specific) psychopathology factors (capturing internalizing, externalizing, and psychotic problems, respectively, independently of general psychopathology) based on nine parental register-based psychiatric diagnoses and violent criminal court convictions. Second, we regressed each offspring outcome on the latent general and three specific factors simultaneously.ResultsThe general psychopathology factor in parents was significantly associated with all 31 offspring outcomes (mean Odds Ratio (OR) = 1.22; range: 1.08–1.40), which means that children whose parents scored one standard deviation above the mean on general psychopathology had, on average, a 23% higher probability of all outcomes. The specific psychotic factor in parents was primarily associated with psychotic-like outcomes (mean OR = 1.17; range: 1.05–1.25), and the specific internalizing factor in parents was primarily associated with offspring internalizing (mean OR = 1.11; range: 1.11–1.13) and neurodevelopmental outcomes (mean OR = 1.07; range: 1.02–1.10). The specific externalizing factor in parents was associated with externalizing (mean OR = 1.27; range: 1.21–1.32) and internalizing outcomes (mean OR = 1.10; range: 1.01–1.13).ConclusionsThe intergenerational transmission of psychiatric conditions across different types of spectra appeared largely attributable to a parental general factor of psychopathology, whereas specific factors were primarily responsible for within-spectrum associations between parents and their offspring. Service providers (e.g., child psychologists, psychiatrists, teachers, and social workers) might benefit from taking the total number of parental mental health problems into account, regardless of type, when forecasting child mental health and social functions.Disclosure of InterestNone Declared

Prenatal Cannabis Use Disorder and Risk of Neurodevelopmental Disorders in Offspring: A Linked Data Cohort

IntroductionCannabis use has been increasing among women of reproductive age in the last few decades. In-utero cannabis exposure could be associated with an increased risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID) during childhood and adolescence; however, existing evidence was generated based on maternal self-report of cannabis use in pregnancy. We conducted a large-scale with data linkage cohort study, in which both exposure and outcome of interests were confirmed using diagnostic tools, ICD-10-AM.ObjectivesThis study aimed to examine the association between prenatal cannabis use disorder (CUD) and neurodevelopmental disorders in offspring using a large-scale cohort study.MethodsWe conducted an administrative health data-based cohort study of 222,569 mother-offspring pairs using linked data obtained from health registries in New South Wales (NSW), Australia. Data were drawn from the NSW Perinatal Data Collection (PDC), which included all live births in the Australian state of NSW between January 2003 and December 2005. These were linked with the NSW in-patient and ambulatory data collections for mothers and offspring. The prenatal cannabis use disorder (exposure) and neurodevelopmental disorders in offspring (outcomes of interest) were measured by using ICD-10-AM. Generalized linear regression with a binomial family model was used to explore the association. We also carried out a modification/interaction effect of low birth weight (LBW), smoking and premature births (PTB), which enhanced the methodological robustness of the study.ResultsThis study found that offspring from mothers with prenatal CUwD had a 98%, 94% and 46% increased risk of ADHD [aRR = 1.98: 95 % CI 1.36 – 2.88], ASD [aRR = 1.94: 95 % CI 1.34 – 2.82], and ID [aRR = 1.46: 95 % CI 1.01 – 2.63] compared to those non-exposed offspring, respectively. We observed a significant interaction effect between CUD during pregnancy and maternal smoking on the risk of childhood ADHD, ASD and ID [CUD*smoking: RR = 5.62: 95 % CI 3.77 – 8.39, RR = 2.72: 95 % CI 1.78 – 4.18, and RR = 2.84: 95 % CI 1.54 – 5.22, respectively]. Furthermore, we also found significant associations between PCUD and ADHD, ASD and ID when interacting with LBW, and PTB.ConclusionsMaternal prenatal CUD is associated with a higher risk of ADHD, ASD, and ID in offspring. The effect of maternal CUD on neurodevelopmental disorders was also found to be stronger when mothers also reported smoking during pregnancy, compared to the individual effects of cannabis use or smoking alone. The findings highlight the importance of implementing preventive strategies to reduce cannabis use in pregnancy.Disclosure of InterestNone Declared

Chd8 haploinsufficiency impacts rearing experience in C57BL/6 mice.

Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8 haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact of Chd8 haploinsufficiency on maternal-offspring interactions. While differences in maternal care as a function of Chd8 genotype have not been studied directly, a previous study showed that pup survival was reduced when reared by Chd8 heterozygous dams compared with wild-type (WT) dams, suggesting altered maternal care as a function of Chd8 genotype. Through systematic observation of the C57BL/6 strain, we first determined the impact of Chd8 haploinsufficiency in the offspring on WT maternal care frequencies across preweaning development. We next determined the impact of maternal Chd8 haploinsufficiency on pup care. Compared with litters with all WT offspring, WT dams exhibited less frequent maternal behaviors toward litters consisting of offspring with mixed Chd8 genotypes, particularly during postnatal week 1. Dam Chd8 haploinsufficiency decreased litter survival and increased active maternal care also during postnatal week 1. Determining the impact of Chd8 haploinsufficiency on early life experiences provides an important foundation for interpreting offspring outcomes and determining mechanisms that underlie heterogeneous phenotypes.

Maternal Seafood Consumption during Pregnancy and Cardiovascular Health of Children at 11 Years of Age.

Nutrition is critical during pregnancy for the healthy growth of the developing infant, who is fully dependent on maternal dietary omega-3 supply for development. Fatty fish, a main dietary source of omega-3, is associated with decreased cardiovascular risk in adults. We conducted a longitudinal study based on a mother-offspring cohort as part of the project Infancia y Medio Ambiente (INMA) in order to assess whether fish intake during pregnancy relates to cardiovascular health in children. A total of 657 women were included and followed throughout pregnancy until birth, and their children were enrolled at birth and followed up until age 11-12. A semi-quantitative food frequency questionnaire was used to assess the daily intake of foods during the 1st and 3rd trimesters of pregnancy. Cardiovascular assessments included arterial stiffness (assessed by carotid-femoral pulse wave velocity [PWV]) and retinal microcirculation (photographic assessment of central retinal arteriolar and venular equivalent [CRAE and CRVE]). The association between maternal fish consumption and cardiovascular outcomes of offspring at 11 years of age was evaluated using multivariable linear regression models. There were no statistically significant differences in any cardiovascular endpoint in children whose mothers had a higher fish consumption during pregnancy compared to those with a lower fish consumption. We found a slightly higher PWV (β = 0.1, 95% CI = 0.0; 0.2, p for trend = 0.047) in children whose mothers had a higher consumption of canned tuna during the 1st trimester of pregnancy. Fish intake during pregnancy was found to be unrelated to the offspring's cardiovascular health at 11 years of age. The beneficial cardiovascular effects of fish consumption during pregnancy on the offspring are still inconclusive.

The Mood and Resilience in Offspring (MARIO) project: a longitudinal cohort study among offspring of parents with and without a mood disorder

BackgroundOne of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors.MethodsMARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected.DiscussionThe MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.

Childhood and adolescence outcomes in offspring to parents with bipolar disorder: the impact of lifetime parental comorbidity, parental sex, and bipolar subtype.

Offspring of parents with bipolar disorder have increased risks of their own psychopathology. However, a large-scale survey of psychiatric, somatic, and adverse social outcomes up to adulthood, which could aid in prioritizing and tailoring prevention, is lacking. It also remains to clarify how risks are modified by other parental factors. Swedish population registers were linked to compare offspring having (N = 24,788) and not having (N = 247,880) a parent with bipolar disorder with respect to psychiatric diagnoses and psychotropic medication, birth-related and somatic conditions, social outcomes, accidents, suicide attempts, and mortality. Individuals were followed until age 18. We estimated the influence of lifetime parental psychiatric comorbidity, bipolar disorder subtype, and sex on outcomes. Children of parents with bipolar disorder had 2-3 times higher risks of all psychiatric diagnoses, except for bipolar disorder, for which the risk was 11-fold. Significantly increased risks were also found for several somatic conditions, low school grades, criminal behavior, victimization, accidents, and suicidal behavior. Adjusting for lifetime parental psychiatric comorbidity attenuated most associations. Offspring of a parent with bipolar disorder type 2 had statistically significantly higher risks of attention deficit hyperactivity disorder, respiratory tract conditions, and accidents compared with offspring of a parent with bipolar disorder type 1. Offspring of mothers with bipolar disorder had higher risks of several psychiatric diagnoses, respiratory tract conditions, low school grades, and accidents compared with offspring of fathers with bipolar disorder. Having two parents with bipolar disorder entailed the highest risks of psychiatric outcomes in offspring. Early intervention and family support are particularly warranted for the offspring of a parent with bipolar disorder in the presence of lifetime parental psychiatric comorbidity, when the parent has bipolar disorder type 2, or when the mother or both parents have bipolar disorder.

Unveiling the impact of maternal gestational diabetes mellitus on cord blood CD71+ erythroid cell transcriptome.

This study reveals the effects of maternal gestational diabetes mellitus (GDM) on the transcriptome of CD71+ erythroid cells (CECs) in cord blood. It highlights the role of CECs in immunosuppressive function and identifies potential mechanisms linking GDM to adverse outcomes in offspring. This understanding might lead to improved strategies for managing and preventing adverse outcomes in infants born to mothers with GDM.

Viral infections in pregnancy and impact on offspring neurodevelopment: mechanisms and lessons learned.

Pregnant individuals with viral illness may experience significant morbidity and have higher rates of pregnancy and neonatal complications. With the growing number of viral infections and new viral pandemics, it is important to examine the effects of infection during pregnancy on both the gestational parent and the offspring. Febrile illness and inflammation during pregnancy are correlated with risk for autism, attention deficit/hyperactivity disorder, and developmental delay in the offspring in human and animal models. Historical viral epidemics had limited follow-up of the offspring of affected pregnancies. Infants exposed to seasonal influenza and the 2009 H1N1 influenza virus experienced increased risks of congenital malformations and neuropsychiatric conditions. Zika virus exposure in utero can lead to a spectrum of abnormalities, ranging from severe microcephaly to neurodevelopmental delays which may appear later in childhood and in the absence of Zika-related birth defects. Vertical infection with severe acute respiratory syndrome coronavirus-2 has occurred rarely, but there appears to be a risk for developmental delays in the infants with antenatal exposure. Determining how illness from infection during pregnancy and specific viral pathogens can affect pregnancy and neurodevelopmental outcomes of offspring can better prepare the community to care for these children as they grow. IMPACT: Viral infections have impacted pregnant people and their offspring throughout history. Antenatal exposure to maternal fever and inflammation may increase risk of developmental and neurobehavioral disorders in infants and children. The recent SARS-CoV-2 pandemic stresses the importance of longitudinal studies to follow pregnancies and offspring neurodevelopment.

Maternal and long-term offspring outcomes of obesity during pregnancy.

Obesity`s prevalence is rising in women of reproductive age worldwide and has become the most common medical condition at this age group. Besides, its occurrence is also rising during pregnancy. This condition not only increases the risk of noncommunicable diseases on the mother, such as cardiovascular disease and diabetes, but also transfers this risk to the offspring. This is a narrative review based on scientific and review articles on the matter. Obesity is associated with an increased risk of gestational diabetes mellitus, gestational hypertension and preeclampsia, venous thromboembolism, infection, and mental health problems. Furthermore, it has an impact on the progress of labor and induction matters. Regarding offspring outcomes, it is related to higher incidence of congenital anomalies, perinatal mortality, and the occurrence of large for gestational age newborns. Still, it has implications on cardiometabolic risk and neurodevelopment in offspring. It is, therefore, imperative to encourage the adoption of healthy lifestyles, especially in the peri-conception and interpregnancy periods. Likewise, there must be support in the multidisciplinary monitoring of these pregnant women to minimize associated complication rates.

First trimester maternal tryptophan metabolism and embryonic and fetal growth: the Rotterdam Periconceptional Cohort (Predict Study).

What is the association between first trimester maternal tryptophan (TRP) metabolites and embryonic and fetal growth? Higher 5-hydroxytryptophan (5-HTP) concentrations are associated with reduced embryonic growth and fetal growth and with an increased risk of small-for-gestational age (SGA), while higher kynurenine (KYN) concentrations are associated with a reduced risk of SGA. The maternal TRP metabolism is involved in many critical processes for embryonic and fetal growth, including immune modulation and regulation of vascular tone. Disturbances in TRP metabolism are associated with adverse maternal and fetal outcomes. This study was embedded within the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective observational cohort conducted at a tertiary hospital from November 2010 onwards. A total of 1115 women were included before 11 weeks of gestation between November 2010 and December 2020. Maternal serum samples were collected between 7 and 11 weeks of gestation, and TRP metabolites (TRP, KYN, 5-HTP, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid) were determined using a validated liquid chromatography (tandem) mass spectrometry method. Serial 3D ultrasound scans were performed at 7, 9, and 11 weeks of gestation to accurately assess features of embryonic growth, including crown-rump length (CRL) and embryonic volume (EV) offline using virtual reality systems. Fetal growth parameters were retrieved from medical records and standardized according to Dutch reference curves. Mixed models were used to assess associations between maternal TRP metabolites and CRL and EV trajectories. Linear and logistic regression models were utilized to investigate associations with estimated fetal weight (EFW) and birthweight, and with SGA, respectively. All analyses were adjusted for potential confounders. Maternal 5-HTP concentrations and the maternal 5-HTP/TRP ratio were inversely associated with embryonic growth (5-HTP, √CRL: β = -0.015, 95% CI = -0.028 to -0.001; 5-HTP 3√EV: β = -0.009, 95% CI = -0.016 to -0.003). An increased maternal 5-HTP/TRP ratio was also associated with lower EFW and birthweight, and with an increased risk of SGA (odds ratio (OR) = 1.006, 95% CI = 1.00-1.013). In contrast, higher maternal KYN concentrations were associated with a reduced risk of SGA in the unadjusted models (OR = 0.548, 95% CI = 0.320-0.921). Residual confounding cannot be ruled out because of the observational design of this study. Moreover, this study was conducted in a single tertiary hospital, which assures high internal validity but may limit external validity. The novel finding that maternal 5-HTP concentrations are associated with a smaller embryo and fetus implies that disturbances of the maternal serotonin pathway in the first trimester of pregnancy are potentially involved in the pathophysiology of fetal growth restriction. The association between higher maternal KYN concentrations and a reduced risk of SGA substantiate the evidence that the KYN pathway has an important role in fetal growth. More research is needed to delve deeper into the potential role of the maternal TRP metabolism during the periconception period and pregnancy outcome for mother and offspring. This study was funded by the Department of Obstetrics and Gynecology and the Department of Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands. The authors have no competing interests to disclose. N/A.

Gestational testosterone excess early to mid-pregnancy disrupts maternal lipid homeostasis and activates biosynthesis of phosphoinositides and phosphatidylethanolamines in sheep

Gestational hyperandrogenism is a risk factor for adverse maternal and offspring outcomes with effects likely mediated in part via disruptions in maternal lipid homeostasis. Using a translationally relevant sheep model of gestational testosterone (T) excess that manifests maternal hyperinsulinemia, intrauterine growth restriction (IUGR), and adverse offspring cardiometabolic outcomes, we tested if gestational T excess disrupts maternal lipidome. Dimensionality reduction models following shotgun lipidomics of gestational day 127.1 ± 5.3 (term 147 days) plasma revealed clear differences between control and T-treated sheep. Lipid signatures of gestational T-treated sheep included higher phosphoinositides (PI 36:2, 39:4) and lower acylcarnitines (CAR 16:0, 18:0, 18:1), phosphatidylcholines (PC 38:4, 40:5) and fatty acids (linoleic, arachidonic, Oleic). Gestational T excess activated phosphatidylethanolamines (PE) and PI biosynthesis. The reduction in key fatty acids may underlie IUGR and activated PI for the maternal hyperinsulinemia evidenced in this model. Maternal circulatory lipids contributing to adverse cardiometabolic outcomes are modifiable by dietary interventions.