Importance of the environment for gestational duration variability and correlation between relatives - results from the Medical Swedish Birth Registry, 1973-2012.
ABSTRACT: It has been suggested that the intergenerational associations in gestational age at delivery are considerably affected by temporal changes in the environmental conditions. We explored whether changing environment affects familial resemblance of gestational age at delivery. Understanding how correlation changes in different settings allows to design better studies aimed to detect genes and environmental factors involved in the parturition process. The Swedish Medical Birth Register was used to retrieve births during 1973-2012. In total, 454,433 parent-child, 2,247,062 full sibling, 405,116 maternal half-sibling and 469,995 paternal half-sibling pairs were identified. A decreasing trend in correlation, associated with increasing age gaps, was observed among all siblings, with the largest drop for full siblings, from ? = 0.32 (95% confidence interval (CI): 0.31, 0.33) for full siblings with one-year gap to ? = 0.16 (95% CI: 0.10, 0.22) for full siblings with age gap above 20 years. A variation in association between full siblings born up to two years apart was observed; estimate ? = 0.28 (95% CI: 0.26, 0.3) in 1973, and ? = 0.36 (95% CI: 0.33, 0.38) in 2012. Observed variability in the association in gestational age at delivery between the relatives with respect to their birth year or age gap suggests the existence of temporally changing environmental factors.
Project description:BACKGROUND:Small for gestational age (SGA) has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce. Maternal antenatal care, including globally reducing the risk of SGA birth, may be key to achieving the Millennium Development Goal of reducing under-5 mortality. We therefore aimed to examine the association between SGA and mortality from 28 days to <18 years using a population-based and a sibling control design. METHODS AND FINDINGS:In a Swedish population study, we identified 3,795,603 non-malformed singleton live births and 2,781,464 full siblings born from January 1, 1973, to December 31, 2012. We examined the associations of severe (<3rd percentile) and moderate (3rd to <10th percentile) SGA with risks of death from 28 days to <18 years after birth. Children born SGA were first compared to non-SGA children from the population, and then to non-SGA siblings. The sibling-based analysis, by design, features a better control for unmeasured factors that are shared between siblings (e.g., socioeconomic status, lifestyle, and genetic factors). Hazard ratios (HRs) were calculated using Cox proportional hazards and flexible parametric survival models. During follow-up (1973-2013), there were 10,838 deaths in the population-based analysis and 1,572 deaths in sibling pairs with discordant SGA and mortality status. The crude mortality rate per 10,000 person-years was 5.32 in children born with severe SGA, 2.76 in children born with moderate SGA, and 1.93 in non-SGA children. Compared with non-SGA children, children born with severe SGA had an increased risk of death in both the population-based (HR = 2.58, 95% CI = 2.38-2.80) and sibling-based (HR = 2.61, 95% CI = 2.19-3.10) analyses. Similar but weaker associations were found for moderate SGA in the population-based (HR = 1.37, 95% CI = 1.28-1.47) and sibling-based (HR = 1.38, 95% CI = 1.22-1.56) analyses. The excess risk was most pronounced between 28 days and <1 year of age but remained throughout childhood. The greatest risk increase associated with severe SGA was noted for deaths due to infection and neurologic disease. Although we have, to our knowledge, the largest study sample so far addressing the research question, some subgroup analyses, especially the analysis of cause-specific mortality, had limited statistical power using the sibling-based approach. CONCLUSIONS:We found that SGA, especially severe SGA, was associated with an increased risk of childhood death beyond the neonatal period, with the highest risk estimates for death from infection and neurologic disease. The similar results obtained between the population- and sibling-based analyses argue against strong confounding by factors shared within families.
Project description:The death of a close relative is associated with an increased mortality risk among the bereaved, but much less is known about the potential association of the death of a sibling in childhood with mortality in this population.To examine the association between sibling death in childhood and subsequent mortality risk.This population-based cohort study of 5?005?029 participants evaluated linked national registers in Denmark (January 1, 1973, through December 31, 2009) and Sweden (January 1, 1973, through December 31, 2008). A total of 2?060?354 Danish and 2?944?675 Swedish children who survived the first 6 months of their life were included. We excluded 14 children who died of the same external cause as their siblings within 30 days. Data were analyzed from November 2, 2015, through October 14, 2016.Participants were classified as exposed if a sibling died in childhood (age <18 years).Poisson regression was used to estimate mortality rate ratio (MRR) with the exposure as a time-varying variable.Among the 55 818 participants who experienced sibling death in childhood (51.5% male and 48.5% female; median age at loss, 7.0 [interquartile range, 3.3-12.1] years), all-cause mortality risk was increased by 71% (MRR, 1.71; 95% CI, 1.57-1.87) during the follow-up of 37 years. The excess mortality risk was observed for groups with specific causes of death, and the higher MRRs were found when the sibling pairs died of the same cause (death due to disease [MRR, 2.16; 95% CI, 1.87-2.49]; death due to external cause [MRR, 1.91; 95% CI, 1.54-2.37]). The increased mortality risk after sibling death was seen across the follow-up period, regardless of the age at bereavement and the type of death among bereaved siblings, but the magnitude of association was stronger during the first year after sibling death (MRR, 2.51; 95% CI, 1.79-3.54). Higher MRRs were found among sibling pairs with the same sex (MRR, 1.92; 95% CI, 1.70-2.18) and close age (MRR, 1.94; 95% CI, 1.58-2.37).Bereavement in childhood because of the death of a sibling was associated with an increased risk for mortality in the short and long term. Health care professionals should be aware of individuals' vulnerability due to sibling death, especially for sibling pairs of close age or the same sex. Social and health care support may help to minimize the potential adverse effects on the bereaved sibling.
Project description:Studies suggest that preterm delivery is a risk factor for early language delays, but knowledge is scarce about the persistence of the delays and whether the association is of a linear kind. To resolve this, effects of confounding risk factors that are both shared within a family and pregnancy specific need to be distinguished from effects of preterm delivery. Our study examines the association between early gestational age and language outcomes, using a sibling-control design.The sample comprises 22,499 siblings from the Norwegian Mother and Child Birth Cohort Study, recruited between 1999 and 2008. Mothers rated child language comprehension and production at 18 and 36 months. Analyses compared siblings discordant on gestational age group (early preterm, delivery at week 22-33; late preterm, 34-36; early term, 37-38; full term, >38) and type of onset of delivery (spontaneous; provider-initiated), and compared these findings with conventional cohort analyses.The findings revealed inverse linear relations between the gestational age groups, and persistent but diminishing language delays. Effects of preterm delivery were substantial on both language production and comprehension at 18 months. By 36 months, the effects of preterm delivery were weaker, but still extensive, in particular for language production in provider-initiated births. When comparing sibling-control with cohort analyses, preterm group was less important among spontaneous births, but remained important in provider-initiated births. Familial and pregnancy risk factors partly explained this.Distinctive factors seem to underlie effects of preterm delivery across spontaneous and provider-initiated births.
Project description:Children born small for gestational age have a higher risk of intellectual disability. We investigated associations of birth weight for gestational age percentile and gestational age with risk of intellectual disability in appropriate-for-gestational-age (AGA) children. We included 828,948 non-malformed term or post-term AGA singleton children (including 429,379 full siblings) born between 1998 and 2009 based on data from the Swedish Medical Birth Register. Diagnosis of intellectual disability after 3 years of age was identified through the Patient Register. Using Cox regression models, we calculated hazard ratios (HRs) with 95% confidence intervals (CIs) of intellectual disability among children with different birth weight percentiles and gestational age in the whole population and in a subpopulation of full siblings. A total of 1688 children were diagnosed with intellectual disability during follow-up. HRs (95% CIs) of intellectual disability for the low birth weight percentile groups (10th-24th and 25th-39th percentiles, respectively) versus the reference group (40th-59th percentiles) were 1.43 (1.22-1.67) and 1.28 (1.10-1.50) in population analysis and 1.52 (1.00-2.31) and 1.44 (1.00-2.09) in sibling comparison analysis. The increased risk for low birth weight percentiles in population analysis was stable irrespective of gestational age. A weak U-shaped association between gestational age and intellectual disability was observed in population analysis, although not in sibling comparison analysis. These findings suggest that among AGA children born at term or post-term, lower birth weight percentiles within the normal range are associated with increased risk of intellectual disability, regardless of gestational age.
Project description:Importance:Preterm birth is associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD); however, it is unclear to what extent this association can be explained by shared genetic and environmental risk factors and whether gestational age at birth is similarly related to inattention and hyperactivity/impulsivity and to the same extent in boys and girls. Objectives:To investigate the association between gestational age at birth and symptoms of ADHD in preschool and school-age children after adjusting for unmeasured genetic and environmental risk factors. Design, Setting, and Participants:In this prospective, population-based cohort study, pregnant women were recruited from across Norway from January 1, 1999, through December 31, 2008. Results of a conventional cohort design were compared with results from a sibling-comparison design (adjusting for genetic and environmental factors shared within families) using data from the Norwegian Mother and Child Cohort Study. Data analysis was performed from October 1, 2017, through March 16, 2018. Exposures:Analyses compared children and siblings discordant for gestational age group: early preterm (delivery at gestational weeks 22-33), late preterm (delivery at gestational weeks 34-36), early term (delivery at gestational weeks 37-38), delivery at gestational week 39, reference group (delivery at gestational week 40), delivery at gestational week 41, and late term (delivery after gestational week 41). Main Outcomes and Measures:Maternally reported symptoms of ADHD in children at 5 years of age and symptoms of inattention and hyperactivity/impulsivity at 8 years of age. Covariates included child and pregnancy characteristics associated with the week of delivery and the outcomes. Results:A total of 113 227 children (55 187 [48.7%] female; 31 708 [28.0%] born at gestational week 40), including 33 081 siblings (16 014 female [48.4%]; 9705 [29.3%] born at gestational week 40), were included in the study. Children born early preterm were rated with more symptoms of ADHD, inattention, and hyperactivity/impulsivity than term-born children. After adjusting for unmeasured genetic and environmental factors, children born early preterm had a mean score that was 0.24 SD (95% CI, 0.14-0.34) higher on ADHD symptom tests, 0.33 SD (95% CI, 0.24-0.42) higher on inattention tests, and 0.23 SD (95% CI, 0.14-0.32) higher on hyperactivity/impulsivity tests compared with children born at gestational week 40. Sex moderated the association of gestational age with preschool ADHD symptoms, and the association appeared to be strongest among girls. Early preterm girls scored a mean of 0.8 SD (95% CI, 0.12-1.46; P = .02) higher compared with their term-born sisters. Conclusions and Relevance:After accounting for unmeasured genetic and environmental factors, early preterm birth was associated with a higher level of ADHD symptoms in preschool children. Early premature birth was associated with inattentive but not hyperactive symptoms in 8-year-old children. This study demonstrates the importance of differentiating between inattention and hyperactivity/impulsivity and stratifying on sex in the study of childhood ADHD.
Project description:Importance:It is unclear if the associations between fetal growth and later mental health conditions remain after controlling for familial factors and psychiatric comorbidity. Objective:To examine the associations between fetal growth and general and specific mental health conditions, controlling for familial factors. Design, Setting, and Participants:This register-based study conducted in Sweden analyzed 546 894 pairs of full siblings born between January 1, 1973, and December 31, 1998. Sibling pairs were followed up through December 31, 2013. First, population-based and within-sibling pair associations (which controlled for time-invariant familial confounders) between fetal growth and the outcomes were estimated. Second, exploratory factor analysis was applied to the outcomes to derive 1 general factor and 4 specific and independent factors. Third, the general and specific factors were regressed on fetal growth. Statistical analysis was performed from March 27, 2017, to October 27, 2018. Main Outcome and Measures:The outcomes were 11 psychiatric diagnoses (depression, anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, bipolar disorder, alcohol abuse, drug use, attention-deficit/hyperactivity disorder, autism, schizophrenia, and schizoaffective disorder) and court convictions of violent crimes. Birth weight (in kilograms) statistically adjusted for gestational age was the exposure. Results:The mean (SD) age of the 1?093?788 participants was 27.2 (6.8) years (range, 15.1-40.9 years) and 51.5% were male. Nine outcomes were significantly associated with birth weight in the population at large: depression (odds ratio [OR], 0.96; 95% CI, 0.95-0.98), anxiety (OR, 0.94; 95% CI, 0.92-0.95), posttraumatic stress disorder (OR, 0.91; 95% CI, 0.89-0.93), bipolar disorder (OR, 0.94; 95% CI, 0.89-1.00), alcohol abuse (OR, 0.89; 95% CI, 0.87-0.91), drug use (OR, 0.83; 95% CI, 0.80-0.85), violent crimes (OR, 0.85; 95% CI, 0.83-0.86), attention-deficit/hyperactivity disorder (OR, 0.88; 95% CI, 0.86-0.90), and autism (OR, 0.95; 95% CI, 0.92-0.97). Only depression (OR, 0.95; 95% CI 0.92-0.98), obsessive-compulsive disorder (OR, 0.93; 95% CI, 0.87-0.99), attention-deficit/hyperactivity disorder (OR, 0.86; 95% CI, 0.82-0.89), and autism (OR, 0.72; 95% CI, 0.69-0.76) remained significantly associated within sibling pairs. An exploratory factor analysis indicated that 1 general and 4 specific factors (capturing anxiety, externalizing, neurodevelopmental, and psychotic conditions) fit the outcomes well. Across almost all sensitivity analyses, an increase in birth weight by 1 kg significantly reduced the general (?, -0.047; 95% CI, -0.071 to -0.023) and the specific neurodevelopmental factors (?, -0.159; 95% CI, -0.190 to -0.128) within sibling pairs. Conclusions and Relevance:Controlling for familial confounders, reduced fetal growth was associated with a small but significant increase in the general factor of psychopathology and a moderate increase in a specific neurodevelopmental factor.
Project description:Studies have found that sibling loss is associated with an increased risk of death from external causes (i.e. suicides, accidents and homicides). Increased psychiatric health problems following bereavement could underlie such an association. We studied the influence of sibling loss during childhood on psychiatric care in young adulthood, adjusting for psychosocial covariates shared by siblings in childhood. A national cohort born in Sweden in 1973-1982 (N?=?701,270) was followed prospectively until 2013. Cox proportional hazards models were used to analyse the association between sibling loss during childhood and psychiatric inpatient and outpatient care identified by the Hospital Discharge Register. After adjustment for confounders, the HRs of psychiatric care in men who experienced sibling loss were 1.17 (95% CI 1.07-1.27) while the associations turned non-significant in women after adjustment for family-related psychosocial covariates, HR 1.07 (95% CI 0.99-1.16). An increased risk was found in men bereaved in early childhood (1.22 95% CI 1.07-1.38) and adolescence (1.27 95% CI 1.08-1.48). Among women, loss of a sibling during adolescence was significantly associated with psychiatric care (1.19 95% CI 1.03-1.36). Increased psychiatric health problems following bereavement could underlie the previously found association between sibling loss and mortality from external causes. Family-related psychosocial conditions shared by siblings in childhood may account for the association between sibling death and psychiatric care in adulthood.
Project description:Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand.To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood.Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data.A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months.The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior.Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale?=?111; performance?=?108; verbal?=?111) and unexposed siblings (scores: full scale?=?111; performance?=?107; verbal?=?111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale?=?-0.2 (95% CI, -2.6 to 2.9); performance?=?0.5 (95% CI, -2.7 to 3.7); and verbal?=?-0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior.Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.
Project description:Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.
Project description:BACKGROUND:Preterm birth (gestational age <37?weeks) has previously been associated with cardiometabolic and neuropsychiatric disorders into adulthood, but has seldom been examined in relation to sleep disorders. We conducted the first population-based study of preterm birth in relation to sleep-disordered breathing (SDB) from childhood into mid-adulthood. METHODS:A national cohort study was conducted of all 4 186 615 singleton live births in Sweden during 1973-2014, who were followed for SDB ascertained from nationwide inpatient and outpatient diagnoses through 2015 (maximum age 43?years). Cox regression was used to examine gestational age at birth in relation to SDB while adjusting for other perinatal and maternal factors, and co-sibling analyses assessed for potential confounding by unmeasured shared familial factors. RESULTS:There were 171 100 (4.1%) persons diagnosed with SDB in 86.0 million person-years of follow-up. Preterm birth was associated with increased risk of SDB from childhood into mid-adulthood, relative to full-term birth (39-41?weeks) [adjusted hazard ratio (aHR), ages 0-43?years: 1.43; 95% confidence interval (CI), 1.40, 1.46; P?<0.001; ages 30-43?years: 1.40; 95% CI, 1.34, 1.47; P?<0.001]. Persons born extremely preterm (<28?weeks) had more than 2-fold risks (aHR, ages 0-43?years: 2.63; 95% CI, 2.41, 2.87; P?<0.001; ages 30-43?years: 2.22; 95% CI, 1.64, 3.01; P?<0.001). These associations affected both males and females, but accounted for more SDB cases among males (additive interaction, P?=?0.003). Co-sibling analyses suggested that these findings were only partly due to shared genetic or environmental factors in families. CONCLUSIONS:Preterm-born children and adults need long-term follow-up for anticipatory screening and potential treatment of SDB.