Associations of parental and perinatal factors with subsequent risk of stress-related disorders: a nationwide cohort study with sibling comparison

Little is known about the contribution of pregnancy-related parental and perinatal factors to the development of stress-related disorders. We aimed to investigate whether parental/perinatal adversities entail higher risks of stress-related disorders in the offspring, later in life, by accounting for genetic and early environmental factors. Based on the nationwide Swedish registers, we conducted a population-based cohort study of 3,435,747 singleton births (of which 2,554,235 were full siblings), born 1973–2008 and survived through the age of 5 years. Using both population- and sibling designs, we employed Cox regression to assess the association between parental and perinatal factors with subsequent risk of stress-related disorders. We identified 55,511 individuals diagnosed with stress-related disorders in the population analysis and 37,433 in the sibling analysis. In the population-based analysis we observed increased risks of stress-related disorders among offspring of maternal/paternal age <25, single mothers, parity ≥4, mothers with BMI ≥ 25 or maternal smoking in early pregnancy, gestational diabetes, and offspring born moderately preterm (GA 32–36 weeks), or small-for-gestational-age. These associations were significantly attenuated toward null in the sibling analysis. Cesarean-section was weakly associated with offspring stress-related disorders in population [hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06–1.12] and sibling analyses (HR 1.10, 95% CI 1.02–1.20). Our findings suggest that most of the observed associations between parental and perinatal factors and risk of stress-related disorders in the population analysis are driven by shared familial environment or genetics, and underscore the importance of family designs in epidemiological studies on the etiology of psychiatric disorders.

Maternal Anxiety and Infants Birthweight and Length of Gestation. A sibling design

Background The overall aim of this study is to examine the effect of prenatal maternal anxiety on birthweight and gestational age, controlling for shared family confounding using a sibling comparison design. Methods The data on 77,970 mothers and their 91,165 children from the population-based Mother, Father and Child Cohort Study and data on 12,480 pairs of siblings were used in this study. The mothers filled out questionnaires for each unique pregnancy, at 17th and 30th week in pregnancy. Gestational age and birth weight was extracted from the Medical Birth Registry of Norway (MBRN). Associations between prenatal maternal anxiety (measured across the 17th and 30th weeks) and birth outcomes (birthweight and gestational age) were examined using linear regression with adjustment for shared-family confounding in a sibling comparison design. Results In the population level analysis the maternal anxiety score during pregnancy was inversely associated with new-born’s birthweight (Beta = -63.8 95% CI: -92.6, -35.0) and gestational age (Beta = -1.52, 95% CI: -2.15, -0.89) after adjustment for several covariates. The association of the maternal anxiety score with birthweight was no longer significant, but remained for maternal anxiety at 30th week with gestational age (Beta = -1.11, 95% CI: -1.82, -0.4) after further adjusting for the shared-family confounding in the sibling comparison design. Conclusion No association was found for maternal prenatal anxiety with birth weight after multiple covariates and family environment were controlled. However, there was an association between prenatal maternal anxiety at 30th week only with gestational age, suggesting a timing effect for maternal anxiety in third trimester.

Cancer risk in individuals with intellectual disability in Sweden: A population-based cohort study

Background A knowledge gap exists about the risk of cancer in individuals with intellectual disability (ID). The primary aim of this study was to estimate the cancer risk among individuals with ID compared to individuals without ID. Methods and findings We conducted a population-based cohort study of all children live-born in Sweden between 1974 and 2013 and whose mothers were born in a Nordic country. All individuals were followed from birth until cancer diagnosis, emigration, death, or 31 December 2016 (up to age 43 years), whichever came first. Incident cancers were identified from the Swedish Cancer Register. We fitted Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of cancer risk in relation to ID after adjusting for several potential confounders. We analyzed ID by severity, as well as idiopathic ID and syndromic ID separately. We performed a sibling comparison to investigate familial confounding. The study cohort included a total of 3,531,305 individuals, including 27,956 (0.8%) individuals diagnosed with ID. Compared with the reference group (individuals without ID and without a full sibling with ID), individuals with ID were in general more likely to be male. The median follow-up time was 8.9 and 23.0 years for individuals with ID and individuals without ID, respectively. A total of 188 cancer cases were identified among individuals with ID (incidence rate [IR], 62 per 1,000 person-years), and 24,960 among individuals in the reference group (IR, 31 per 1,000 person-years). A statistically significantly increased risk was observed for any cancer (HR 1.57, 95% CI 1.35–1.82; P < 0.001), as well as for several cancer types, including cancers of the esophagus (HR 28.4, 95% CI 6.2–130.6; P < 0.001), stomach (HR 6.1, 95% CI 1.5–24.9; P = 0.013), small intestine (HR 12.0, 95% CI 2.9–50.1; P < 0.001), colon (HR 2.0, 95% CI 1.0–4.1; P = 0.045), pancreas (HR 6.0, 95% CI 1.5–24.8; P = 0.013), uterus (HR 11.7, 95% CI 1.5–90.7; P = 0.019), kidney (HR 4.4, 95% CI 2.0–9.8; P < 0.001), central nervous system (HR 2.7, 95% CI 2.0–3.7; P < 0.001), and other or unspecified sites (HR 4.8, 95% CI 1.8–12.9; P = 0.002), as well as acute lymphoid leukemia (HR 2.4, 95% CI 1.3–4.4; P = 0.003) and acute myeloid leukemia (HR 3.0, 95% CI 1.4–6.4; P = 0.004). Cancer risk was not modified by ID severity or sex but was higher for syndromic ID. The sibling comparison showed little support for familial confounding. The main study limitations were the limited statistical power for the analyses of specific cancer types, and the potential for underestimation of the studied associations (e.g., due to potential underdetection or delayed diagnosis of cancer among individuals with ID). Conclusions In this study, we found that individuals with ID showed an increased risk of any cancer, as well as of several specific cancer types. These findings suggest that extended surveillance and early intervention for cancer among individuals with ID are warranted.

P–724 The association between use of assisted reproductive techniques and childhood asthma: a Swedish nationwide register-based cohort study

Study question Are the previously reported greater risks of childhood asthma in children conceived by assisted reproductive techniques due to the intervention or unmeasured parental confounding? Summary answer After accounting for both measured and unmeasured parental factors we found no indication that the use of assisted reproductive techniques increases children’s risk of asthma. What is known already Several earlier studies have reported a higher risk of childhood asthma among children conceived by ART. However, only one previous study has attempted a sibling comparison to account for infertility as well as parental background factors, and their findings need to be replicated. Little is thus known on what underlies the higher risk of childhood asthma. Study design, size, duration In this nationwide register-based cohort, we identified all 1,671,532 live births between 1997 and 2013 in the Swedish Medical Birth Register (MBR) and followed them to the end of 2018. Participants/materials, setting, methods Infertility and ART use were ascertained from IVF clinic reporting, clinical diagnosis, and maternal self-report during the first antenatal visit. Childhood asthma was identified from diagnosis in hospitalization and outpatient specialist care records, and dispensations of asthma medication. Cox proportional hazard regression was used to estimate the association of ART and asthma in the population, in children of couples with known infertility, and in a sample of siblings conceived with and without ART (differentially exposed). Main results and the role of chance Of the 1,671,532 live births in the cohort, 11.7% were born to couples with known infertility, and 3.5% were conceived with ART. Compared with all other children, children conceived by ART had a small, elevated risk of asthma (adjusted hazard ratio (aHR)=1.14, 95% Confidence interval (CI) 1.11 to 1.16). When the comparison was restricted to children of couples with known infertility the difference in risk was even smaller (aHR=1.07, 95% CI 1.05 to 1.10), and in the comparison of siblings conceived with and without ART no difference in risk was seen (aHR=0.98, 95% CI 0.86 to 1.13). Among children conceived with ART, those in which intra-cytoplasmic sperm injection (ICSI) had been used had a slightly lower risk of asthma (aHR=0.93, 95% CI 0.90 to 0.97), and no difference in risk was seen between use of fresh and frozen-thawed embryo transfer. Limitations, reasons for caution Sibling comparison is sensitive to potential misclassification, unmeasured confounding and carryover effects, so should be interpreted with this in mind. Differences in treatment implementation across time and settings could affect the ability to extrapolate the conclusions to another clinical context (where e.g., single-embryo transfer policy is not implemented). Wider implications of the findings: This study found a modestly elevated risk of asthma in children conceived with ART to be largely explained by confounding from parental background factors. There were further no indications of adverse influence from increasingly utilized ART procedures such as ICSI or embryo-freezing, with respect to asthma in childhood. Trial registration number Not applicable

The Effect of Smoking during Pregnancy on Severity and Directionality of Externalizing and Internalizing Symptoms: A Genetically Informed Approach

The objective was to examine the association between maternal smoking during pregnancy (SDP) and (I) severity and (II) directionality of externalizing and internalizing symptoms in a sample of sibling pairs while rigorously controlling for familial confounds. The Missouri Mothers and Their Children Study is a family study (N = 173 families) with sibling pairs (aged 7 to 16 years) who are discordant for exposure to SDP. This sibling comparison study is designed to disentangle the effects of SDP from familial confounds. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount). Principal component analysis of externalizing and internalizing behavior, assessed with the Child Behavior Checklist and Teacher Report Form, was used to create symptom severity and directionality scores. The variance in severity and directionality scores was primarily a function of differences between siblings (71% and 85%, respectively) rather than differences across families (29% and 15%, respectively). The severity score that combines externalizing and internalizing symptom severity was not associated with SDP. However, a significant within-family effect of SDP on symptom directionality (b = 0.07, p = 0.04) was observed in the sibling comparison model. The positive directionality score indicates that SDP is associated with differentiation of symptoms towards externalizing rather than internalizing symptoms after controlling for familial confounds with a sibling comparison model. This supports a potentially causal relationship between SDP and externalizing behavior.

Sibling comparison designs, are they worth the effort?

The paper by Dr von Ehrenstein et al (Am J Epidemiol. 2020;000(00):000–000) adds to the large and growing literature on the potentially causal association between prenatal exposure to maternal smoking and neuropsychiatric health. In addition to statewide, prospectively collected data, a particular strength was their ability to perform a sibling comparison design, contrasting the rate of autism spectrum disorder in siblings discordantly exposed to maternal smoking. Unfortunately, the estimate from the sibling pairs could neither confirm nor refute the conclusions based on the full cohort. Interpretation was hampered by broad confidence limits, and even had power been higher, the authors acknowledge a range of potential biases that would have made it difficult to draw any firm conclusions from a similarity or difference in the sibling pair estimate and estimate from the full cohort. Was the addition of the sibling comparison actually worth the effort? In this commentary, I will briefly summarize the benefits and limitations of this design, and, with some caveats, argue that its inclusion in the study by Dr von Ehrenstein et al. was indeed a strength and not just an ornamentation.