Maternal anxiety or depression and cognitive ability in young male offspring: A population-based cohort study using cognitive test scores from the Danish Conscription Board Examination

Maternal anxiety or depression and cognitive ability in young male offspring: A population-based cohort study using cognitive test scores from the Danish Conscription Board Examination | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Maternal anxiety or depression and cognitive ability in young male offspring: A population-based cohort study using cognitive test scores from the Danish Conscription Board Examination Tanja Gram Petersen, Rikke Wesselhoeft, Gunhild Tidemann Okholm, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6252560/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Purpose We aimed to study how the timing of incident maternal emotional disorders is associated with male offspring's cognitive ability in early adulthood using cognitive test data from military conscription in a population-based cohort. Methods We linked all males (conscripts) born in Denmark 1996–2001 to parental hospital records to identify anxiety or depression (emotional disorders). Linear regression assessed the association between the timing of the first maternal diagnosis (before, during, or after birth (0–1, 1–5, 6–17 years)) and cognitive ability measured at the Danish Conscription Board Examination 2014–2019. Paternal emotional disorders served as negative controls to differentiate maternal pregnancy exposures from genetic and postnatal influences. Results The study included 119,387 males, with 9,959 (8.3%) having mothers diagnosed with emotional disorders. Offspring exposed to maternal emotional disorders had lower cognitive test scores (ranging from − 0.22 to -0.10 standard deviations (SD) lower than unexposed) at mean age 18, particularly if the mother was diagnosed during pregnancy (-0.22 SD, 95% CI: -0.36; -0.08). Paternal emotional disorders were also linked to a lower cognitive test score, but showed more consistent associations across all time points (-0.18 to -0.14 SD lower than unexposed). Conclusion Maternal emotional disorders were overall associated with male offspring's long-term cognitive ability. Paternal disorders showed similar associations. While the findings require cautious interpretation, the findings suggest a weak signal of a window of sensitivity for maternal disorders during gestation, with no equivalent signal for paternal disorders. We encourage similar studies with female offspring. Depression anxiety cognition intrauterine exposure pregnancy maternal health Figures Figure 1 Figure 2 Introduction Anxiety and depressive disorders, onward named emotional disorders, are common among women during the reproductive years [ 1 , 2 ]. The perinatal period, which encompasses pregnancy and the first year following delivery, is particularly associated with a high prevalence of emotional disorders, including postpartum depression. Up to one in four women will experience anxiety or depression during this time [ 2 – 4 ], and for many, the symptoms persist throughout the offspring’s early childhood [ 5 ]. Emerging research suggests that maternal emotional disorders negatively affect various child developmental outcomes, including cognitive ability [ 6 – 14 ]. The prenatal period is crucial for the brain development. Maternal emotional disorders during this period may adversely influence fetal brain development, and potentially impact later cognitive ability [ 15 , 16 ]. These effects may result from hormonal changes, such as elevated cortisol levels [ 16 – 19 ], and from suboptimal lifestyle factors [ 20 ], which can compromise the intrauterine environment and potentially impair long-term cognitive development [ 15 , 16 ]. Additionally, genetics and the postnatal familial environment, including parenting quality, play significant roles in linking maternal emotional disorders and child cognition [ 9 , 12 , 13 , 21 – 23 ]. Although the timing of maternal emotional disorders is considered important, it is unclear at what time maternal emotional disorders exert the greatest influence on offspring cognitive ability and whether in-utero exposure increase vulnerability. Observational studies on the timing of maternal emotional disorders and offspring cognitive ability, measured by IQ, have produced inconsistent findings: some suggest that prenatal influences increase vulnerability [ 7 , 10 , 16 ], while others do not [ 6 , 23 – 26 ]. Most previous studies focus on cognitive outcomes in childhood only [ 6 , 7 , 10 , 13 , 16 , 23 – 26 ], but follow-up and assessment in youth/adulthood may better represent the life-course impact on cognitive ability since the genetic impact on IQ becomes more pronounced with advancing age [ 27 ]. Only a few studies have examined maternal emotional disorders in relation to offspring cognitive ability while following the offspring until adolescence [ 14 , 23 , 28 , 29 ]. All of these studies rely on relatively small sample sizes. Moreover, most use maternal symptom reports, which include non-severe or non-clinical conditions of emotional disorders, and do not assess prenatal exposure. To address the evidence-gab, we aimed to examine how the timing of incident psychiatric diagnosis of maternal emotional disorders is associated with male offspring's cognitive ability in early adulthood in Danish conscripts, which represent a large population-based cohort. Our priori hypothesis was that children born to mothers with anxiety or depression during pregnancy would show a more pronounced association compared to mothers diagnosed after the child was born due to a potentially increased vulnerability with in-utero exposure. Methods In Denmark, all young adult men are legally required to undergo assessments to determine their suitability for military service, including a cognitive test - at the Danish Conscription Board Examination. Furthermore, the nationwide Danish Patient Registry holds information on hospital diagnoses on the mothers of conscripts. Using these data, we conducted a population-based cohort study on males born in Denmark during 1996–2001 to examine the association between maternal emotional disorders before, during, or after pregnancy and offspring cognitive ability, along exploring paternal influences as a negative control analysis. Data sources All residents in Denmark are assigned a unique personal identification number, which enables the linkage on an individual level of various registers [ 30 ]. We derived data from the following Danish nationwide registers: The Danish Conscription Registry which maintains information on the examinations for military recruitment [ 31 ]. The registry includes data on all males in Denmark, excluding those with documented conditions such as epilepsy, type I diabetes, intellectual disabilities, severe psychiatric illness, and other conditions, which, a priori, disqualify them from military service [ 31 ]. The Danish Medical Birth Register (the Birth Register) [ 32 ], which enables linkage to biological parents and holds pregnancy- and birth-related information, including date of birth and gestational age. The Danish National Patient Registry (the Patient Register), which contains information on all inpatient hospital contacts since 1977 and outpatient hospital contacts since 1995. It informed on the date of hospital contact and diagnoses coded according to the International Classification of Diseases, version 8 (ICD-8) until 1994 and version 10 (ICD-10) from 1995 onward [ 33 ]. We also employed the Danish Psychiatric Central Research Register (the Psychiatric Register) to derive data on psychiatric hospital contacts prior to 1995 with diagnoses coded according to ICD-8 [ 34 ]. The Danish Civil Registration System Register provided data on demographic factors [ 30 ], while socioeconomic registers at Statistics Denmark provided data on parental socioeconomic data [ 35 , 36 ]. Study population In the Birth Register, sex is designated at birth and binary categorized (male/female). In this register, we identified all males (N = 205,828) born in Denmark between January 1, 1996, and December 31, 2001 to form the study population. Males who died or immigrated before the age of 18 and those not assessed at the Conscription Board Examinations between January 1, 2014, and December 31, 2019 were excluded. We also excluded individuals with missing data on the Danish military cognitive test, with missing information necessary to calculate the pregnancy period, or with missing maternal baseline characteristics. The offspring constituted the study unit, and each mother could be included multiple times if she had more than one son represented in the study population. Seventeen percent of the mothers were represented with more than one son. Exposure We defined maternal emotional disorders by an in- or outpatient diagnosis of either an anxiety or a depressive disorder in the Patient Register or the Psychiatric Register. We included the following codes: Unipolar depressive disorders: F32-F33*(ICD10) and 296.09, 298.29, 300.49, 301.19 (ICD8) and anxiety disorders: F40-F48* (ICD10) and 300.x9 (minus 300.49), 305.x9, 305.68, 307.99 (ICD8). The timing of the incident maternal emotional disorder diagnosis was determined based on the date of the first (ever) hospital contact with a diagnosis of anxiety or depressive disorder. The timing was categorized into six groups: 1) no hospital contact, 2) before pregnancy, 3) during pregnancy, 4) within the first year after birth, 5) 1–5 years after birth, and 6) 6–17 years after birth. Data from the Birth Register was used to determine pregnancy periods, defined as the time from conception (calculated as the day of delivery minus gestational age) to delivery. Outcome The outcome measure was cognitive ability assessed by the Danish military cognitive test, Børge Priens Prøve (BPP). The BPP is a group-administered paper-and-pencil cognitive test used as an assessment tool to evaluate individuals' eligibility for military service in Denmark since the 1950s [ 37 , 38 ]. The BPP comprises four subtests assessing logical, verbal, numerical, and spatial reasoning abilities [ 37 , 38 ] and it correlates (0.82) with the full-scale Wechsler Adult Intelligence Scale [ 39 ]. The total BPP score range from 0 to 78 and, for the outcome measure, we used the score per standard deviation (SD) derived from the study population. The total BPP-scores was obtained from the Danish Conscription Registry. Covariates Baseline was defined as the conception date of the pregnancy for each offspring under study.We derived information on birth year (1996–1998, 1999–2001) and primiparity (no, yes) for the index pregnancy from the Birth Register. Maternal age (≤ 20, 21–25, 26–30, 31–35, 36–40, ≥ 41 years) and maternal cohabitation status at baseline (single vs. living with a partner/married) were derived from the Danish Civil Registration System. The highest maternal educational degree at baseline (lower secondary, upper secondary, post-secondary) was obtained from Statistics Denmark. Additionally, we used data from Statistics Denmark the year prior to the baseline on family equivalent disposable income, categorized into tertiles for each baseline year, and maternal occupation (employed, unemployed/receiving social benefits, student). Furthermore, we defined comorbidity in mothers based on the Charlson Comorbidity Index (CCI) [ 40 ] with updated weights according to Quan 2011 [ 41 ]. For this, we used primary and secondary hospital diagnosis codes (ICD8 and ICD10 codes) with a ten-year look-back period prior to baseline recorded in the Patient Register. The history of other maternal psychiatric disorders (no, yes) was identified through psychiatric hospital diagnoses (ICD10: F00-F31*, F34-F39*, F50-F99*(ICD10) and ICD8: 290–315 (minus 296.09, 298.29, 300.49, 301.19, 300.x9, 305.x9, 305.68, 307.99)) from the Patient Register and psychiatric Register. Statistical analysis Baseline characteristics were presented as frequencies for categorical and binary variables and as medians with interquartile-range for continuous variables. To assess baseline comparability between exposure groups, we computed standardized mean differences (SMD) using dummy-variables (no hospital contact vs. the different timing of incident diagnosis). The SMD compares the difference in means in units of the pooled standard deviation [ 42 ]. To balance differences in baseline characteristics between the exposure groups, we computed stabilized inverse probability weights (IPW). First, we used a multinomial logistic regression model, including the exposure variable of onset of maternal emotional disorder as the dependent variable, to determine the probability of exposure given baseline characteristics. The covariates were selected based on Directed Acyclic Graphs and included potential confounders: maternal age (included as restricted cubic splines), cohabitation status, primiparity, birth year of the child, family income, highest maternal educational degree, maternal occupational status, maternal CCI, and other maternal psychiatric history. Then, the IPW for each individual was calculated as the inverse of the probability of being exposed conditional on observed covariates. After applying the IPWs to the study population, the balance of baseline characteristics was evaluated, considering a SMD of less than 10% as acceptable [ 42 ]. We used linear regression analysis to estimate the mean differences in the offspring cognitive test scores according to the timing of maternal incident emotional disorders. Normality was assessed through visual inspection and was not violated. IPW-adjusted estimates were presented with 95% confidence intervals (CIs), calculated using robust variance estimators to account for weights and sibling dependency. We performed a post hoc analysis to test trends in the primary results by including the categorized timing variables of the emotional disorders as a continuous variable in the regression model. We examined whether the association between the timing of maternal incident emotional disorders and mean offspring cognitive test score was modified by the child’s birth year, by conducting analyses stratified by birth years in the following two groups 1996–1998 and 1999–2001, and by testing the interaction term between exposure and birth year. We also examined the association after stratifying by parity and tested the interaction between exposure and parity. To assess the importance of the intrauterine environment, we employed a negative control model using fathers. This model examined the association between the timing of paternal incident emotional disorders and offspring cognitive test scores. We identified biological fathers through the Birth Register. If the fathers were not listed in this register, legal fathers at the time of birth were identified through the Danish Civil Registration System. We conducted a sensitivity analysis, adjusting the association between maternal emotional disorders and cognitive for paternal psychiatric history and paternal emotional disorders, and vice versa when paternal emotional disorders was the exposure. Finally, we conducted a sensitivity analysis, adding information on filled prescriptions of antidepressants and anxiolytics (Anatomical Therapeutic Chemical (ATC) classification codes and N06A (antidepressants) and N05BA (anxiolytics)) to the exposure definition when assessing maternal emotional disorders and offspring cognitive test score. Most cases of emotional disorders are diagnosed and treated in general practice in Denmark and only the most severe cases are captured in the Danish National Patient Registry. Also, this approach account for any latency period from emotional disorder is first treated to a potential hospital diagnosis is registered [ 43 ]. In this analysis, the timing of incident maternal emotional disorder was determined by the date of first filled prescription or the date of the initial hospital diagnosis, whichever came first. Information on filled prescriptions was derived from the Danish National Prescription Registry, which contains data on all prescription drugs dispensed at outpatient pharmacies since 1995 and include date of dispensing and medications classified according to the ATC Classification System [ 44 ]. Data was analyzed using Stata BE 18. Registration The project was registered in OSF in July 2024 ( https://doi.org/10.17605/OSF.IO/SV7W4 ) Results Characteristics of the study population We identified 205,828 males born in Denmark between 1996 and 2001. We excluded 7708 individuals who died or emigrated before the age of 18 years and 62,889 who did not attend the Conscription Board Examinations between 2014 and 2019, largely due to postponement. After also excluding 7605 with missing cognitive test scores (BPP) and 8239 with missing information on pregnancy periods or covariates, 119,387 men remained eligible and constituted the study population (Fig. 1 ). The mean age of the study population at the Conscription Board Examination was 18 years (SD = 0.7). Within the cohort, 9959 mothers (8.3%) had had incident diagnosis of an emotional disorder at any time up to the child turned 18 years. Twelve percent (n = 1233) of these were first (ever) diagnosed before pregnancy, 2.5% during pregnancy (n = 251), and 4.8% within the first year postpartum (n = 480). The prevalence of emotional disorders was higher among women who gave birth in 1999–2001 compared to those who gave birth in 1996–1998. Notably, a greater proportion of women in the later period were diagnosed before or during pregnancy compared to those in the earlier period (Table 1 ). Mothers with emotional disorders were more likely to be primiparous compared to those without, except when the first diagnosis occurred during pregnancy (Table 1 ). Mothers with emotional disorders were also younger, more often single, had lower family income and educational levels, were more frequently unemployed or receiving social benefits, and had a higher prevalence of comorbidities compared to mothers without such diagnoses. After applying the IPW, characteristics of the cohorts were similar with SMD below the 0.1 cutoff, although minor variation in baseline characteristics remained (Table 1 and online Table 2). Association between maternal emotional disorders and offspring cognitive test score The mean cognitive test score was 40.9 (95% CI: 40.8; 40.9) in unexposed offspring. Maternal emotional disorders were associated with lower cognitive test scores regardless of the timing of diagnosis. The lowest mean cognitive test score was observed if the mother had an incident emotional disorder during pregnancy (mean cognitive test score 38.1, 95% CI: 37.1; 39.2). After adjustment, the mean cognitive test score of these offspring was 0.22 SD lower (-0.22 SD, 95% CI: -0.36; -0.08) than in offspring where the mother had no maternal emotional disorder (Fig. 2 ). The post hoc trend-analysis showed a statistically significant trend (p < 0.000) when pre-pregnant Table 1 Baseline characteristics of the study population Characteristics Timing of incident diagnosis of maternal emotional disorder No hospital contact N = 109,428 Before pregnancy N = 1233 During pregnancy N = 251 First year after birth N = 480 1–5 years after birth N = 2345 6–17 years after birth N = 5650 SMD raw SMD IPW adjusted n (%) n (%) n (%) n (%) n (%) n (%) Birth year 0.135 0.071 1996-1998 a 65308 (92.2) 532 (0.8) 137 (0.2) 254 (0.4) 1311 (1.9) 3298 (4.7) 1999-2001 a 44120 (90.9) 701 (1.4) 114 (0.2) 226 (0.5) 1034 (2.1) 2352 (4.8) Primiparity 45381 (41.5) 517 (41.9) 101 (40.2) 215 (44.8) 1059 (45.2) 2374 (42.0) 0.047 0.023 Maternal age, Median [Q1;Q3] 29.0 [26.0;32.0] 29.0 [24.0;33.0] 28.0 [24.0;32.0] 28.0 [25.0;32.0] 27.0 [23.0;31.0] 27.0 [23.0;30.0] 0.183 0.032 ≤20 3657 (3.3) 92 (7.5) 21 (8.4) 34 (7.1) 232 (9.9) 594 (10.5) 21–25 22422 (20.5) 285 (23.1) 55 (21.9) 116 (24.2) 733 (31.3) 1668 (29.5) 26–30 45843 (41.9) 386 (31.3) 85 (33.9) 168 (35.0) 786 (33.5) 1995 (35.3) 31–35 29408 (26.9) 337 (27.3) 64 (25.5) 127 (26.5) 464 (19.8) 1108 (19.6) 36–40 7499 (6.9) 124 (10.1) 23 (9.2) 32 (6.7) 125 (5.3) 268 (4.7) ≥41 599 (0.5) 9 (0.7) 3 (1.2) 3 (0.6) 5 (0.2) 17 (0.3) Not living with a partner/unmarried 9561 (8.7) 267 (21.7) 66 (26.3) 67 (14.0) 419 (17.9) 898 (15.9) 0.202 0.050 Family income 0.199 0.054 Low tertile 35222 (32.2) 615 (49.9) 125 (49.8) 170 (35.4) 1074 (45.8) 2716 (48.1) Midle tertile 37649 (34.4) 352 (28.5) 67 (26.7) 172 (35.8) 721 (30.7) 1719 (30.4) High tertile 36557 (33.4) 266 (21.6) 59 (23.5) 138 (28.7) 550 (23.5) 1215 (21.5) Maternal highest educational degree 0.241 0.074 Lower secondary 23070 (21.1) 531 (43.1) 94 (37.5) 151 (31.5) 1014 (43.2) 2488 (44.0) Upper secondary 55015 (50.3) 472 (38.3) 104 (41.4) 218 (45.4) 933 (39.8) 2282 (40.4) Post-secondary 31343 (28.6) 230 (18.7) 53 (21.1) 111 (23.1) 398 (17.0) 880 (15.6) Unemployed/receiving social benefits 20944 (19.1) 495 (40.1) 88 (35.1) 125 (26.0) 844 (36.0) 2179 (38.6) 0.225 0.062 CCI, ≥2 517 (0.5) 13 (1.1) < 3 < 3 29 (1.2) 38 (0.7) 0.083 0.042 Other psychiatric historic 431 (0.4) 307 (24.9) 19 (7.6) 18 (3.8) 71 (3.0) 107 (1.9) 0.341 0.164 SMD: Standardized mean differences, IPW: Inverse probability weighting, CCI: Charlson Comorbidity Index a row percentages diagnoses were excluded: The strongest association was observed for maternal emotional disorders during pregnancy, which weakened over time after birth. We observed the same patterns in the analyses stratified by birth cohort as in the primary analyses, except emotional disorders diagnosed within the first year postpartum were not associated with change in offspring cognitive test score in the birth cohort 1999–2001 (-0.01 SD, 95% CI: -0.15;0.12) (p-value for interaction < 0.01) (online Table 3). When stratified by parity, the association was strongest for exposure during gestation in both primiparous and multiparous. Maternal diagnoses in the first postpartum year were not associated with offspring cognitive test scores among multiparous mothers (online Table 4), but the interaction was statistically insignificant. Overall, the estimates were less precise in the stratified analyses than in the primary analyses due to the smaller sample sizes and reduced statistical power. Additional adjustment for paternal emotional disorders and paternal history of other psychiatric disorders did not change the estimates for the association between maternal emotional disorders and offspring cognitive test score (online Table 5). When expanding the definition of maternal emotional disorders to also include filled prescription of antidepressants or anxiolytics, more mothers were classified as incident cases of emotional disorders (n = 43,554), (online Table 6). The adjusted mean differences remained comparable to the main analysis, but no stronger association was observed for the pregnancy period. Association between paternal emotional disorders and offspring cognitive test score We included 115,526 offspring with complete paternal information on covariates in the negative control analysis using paternal emotional disorders as the exposure (Fig. 1 ). Five percent (n = 6112) of the fathers were diagnosed with emotional disorders before their child turned 18 years old. Offspring exposed to paternal emotional disorders had lower mean cognitive test scores compared to unexposed, with consistent strengths of association regardless of the timing. Adjusted mean differences per SD ranged from − 0.14 (95% CI: -0.23;-0.04) before pregnancy to -0.18 (95% CI: -0.22;-0.15) 6–17 years after the child was born birth (Fig. 2 ). Additional adjustment for maternal emotional disorders and maternal psychiatric history did not affect the estimates (online Table 7). Discussion In this large population-based sample, we find that maternal emotional disorders are associated with male offspring cognitive ability in early adulthood, as measured by the Danish military cognitive test (Danish: “Børge Priens Prøve”). The association was present regardless of the time of onset, but it was strongest when maternal emotional disorders were diagnosed during pregnancy, although this estimate also showed the greatest statistical imprecision. Likewise and noteworthy, paternal emotional disorders were also associated with offspring cognitive ability - with consistent strength across different time points for exposure. In absolute terms, the difference in cognitive test score (ranging from 0 to 78) was 2.7 points between offspring unexposed to maternal emotional disorder and those exposed during pregnancy. While these effect sizes are relatively small and may not be clinically relevant for the individual, the potential population-level impact of reducing the diagnostic burden may remain important, given the influence of cognitive ability on life outcomes such as socioeconomic or educational outcomes [ 45 ]. We hypothesized a stronger association with emotional disorders diagnosed during pregnancy compared to other time periods due to a potential increased vulnerability with in-utero exposure. One proposed mechanism is that severe anxiety and depression interfere through altered cortisol levels [ 17 , 46 , 47 ] with fetal brain development, potentially impacting later cognitive ability [ 15 , 16 , 19 ]. Specifically, elevated maternal cortisol levels can reduce the activity of the placental enzyme 11β-HSD2, which converts cortisol to inactive cortisone, exposing the fetus to harmful levels of glucocorticoid signaling [ 19 , 48 ]. Alternative mechanisms include unhealthy lifestyle choices associated with perinatal depression [ 20 ]. Such choices could - independent of cortisol - adversely affect the intrauterine environment, potentially impacting the child's long-term cognitive development [ 15 , 16 ]. Our observation of the strongest association with maternal exposure during pregnancy, coupled with the absence of a similar finding for paternal exposure during the same period, provides a subtle signal of increased vulnerability in offspring exposed in utero. Additionally, emotional disorders tend to be recurrent and for up to 20–30% of patients it develops into a chronic condition [ 5 , 49 , 50 ], and the significant test for trend with maternal emotional disorders could hint an accumulating effect, due to longer exposure duration. Regardless, the effect estimate for exposure diagnoses during pregnancy should be interpreted with caution due to the statistical uncertainty. In our study, paternal and maternal emotional disorders during the offspring’s childhood had comparable associations with cognitive ability in the offspring at age 18 years. Parental emotional disorders are associated with genetic factors and postnatal familial influences, which are difficult to segregate and important factors influencing offspring neurodevelopment [ 9 , 23 , 27 , 51 ]. For example, evidence has demonstrated that mothers with depression more often have reduced mental resources for childcare and exhibit more negative emotions compared to mothers without depression [ 21 , 22 ]. Disregarding a maternal or paternal origin, reduced parent-infant interactions could adversely affect child development postpartum and the subsequent cognitive ability [ 9 , 12 , 13 , 21 , 23 , 51 ]. The existing evidence regarding the timing of maternal emotional disorders and cognitive ability remains inconclusive [ 6 , 7 , 10 , 12 , 16 , 23 – 25 ]. Some studies suggest that the prenatal period may be more sensitive than the postnatal period [ 7 , 10 , 52 ]. This was suggested in the Avon Longitudinal Study, but the association between maternal self-reported depression and child IQ weakened and became statistically imprecise after adjusting for multiple confounders [ 7 ]. Our study found only a weak hint of a sensitive period for prenatal exposure. In contrast to our findings, others have found a stronger association with postnatal exposure when assessing cognitive outcomes [ 12 , 23 , 53 ]. Overall, there is a notable lack of studies with repeated measurements to investigate developmental trajectories and critical periods, and many studies fail to control for all known confounders or are based on small sample sizes. A key strength of our study is the use of a large, population-based cohort followed to adulthood, offering a more comprehensive view of life-course impacts on cognitive ability than childhood-only assessments. The Conscription Board Examination is mandatory for Danish males. Only a few are exempt from conscription a priori, such as those with severe somatic or psychiatric conditions. Postponement for educational reasons may primarily explain the relatively high non-attendance rate between 2014 and 2019, particularly among the latest birth cohorts, where the associations between pre- and postnatal influences and offspring cognitive ability were attenuated. Another strength is the use of a standardized cognitive measure, the Børge Priens Prøve (BPP), which correlates with the Wechsler Adult Intelligence Scale [ 39 ], ensuring reliable and valid cognitive measurements. Finally, a key advantage is the inclusion of fathers in a negative control model, which helps separate in utero exposure from genetic and environmental influences. Our study also has limitations. First, females were not included in the study because military service is voluntary for females, resulting in a non-representative sample of women. Thus, our findings are generalizable only to male offspring. Additionally, there is a potential misclassification of the exposure, as anxiety and depression are often underdiagnosed if only hospital records are used [ 43 ] and onset may be misestimated due to the latency between symptoms and the psychiatric diagnosis. To address this, we used filled prescriptions for anxiety/depression medication as a proxy for emotional disorders in a sensitivity analysis. The absence of a stronger association for emotional disorders during pregnancy compared to other periods may suggest antenatal vulnerability only emerges with severe disorders or that psychopharmacology mitigates fetal impact. Furthermore, the analytic choice of using “incident diagnosis” classified six mothers with records of hospital diagnoses during pregnancy as having the disorder “before pregnancy”, which can have resulted in a dilution of the association for the pregnancy period. Finally despite adjusting for various confounders, it is important to consider that poorly measured or unmeasured factors, such as maternal IQ and psychosocial stressors, may have influenced the associations. Conclusion This large population-based cohort study shows a moderate association between maternal emotional disorders and male offspring's cognitive ability at age 18 years. The association of paternal emotional disorders largely resampled the association found for maternal disorders. While the findings should be interpreted with caution, we observed a weak indication of a sensitive period for maternal disorders during pregnancy, with no comparable pattern for paternal emotional disorders. The cognitive differences observed in this study are small and unlikely to be clinically relevant, but they may have broader implications at the population level. We encourage similar studies in other cohorts and the inclusion of female offspring. Declarations Ethical approval The manuscript does not contain clinical studies or patient data. By Danish law, studies based solely on register data do not require ethical approval and data from the Danish national registers can be used for research proposes without informed consent from participants. This study was performed in line with the principles of the Declaration of Helsinki. Funding The study was funded by Helsefonden [Grant No. 23-B-0188]. Competing interests MB and TGP have received salary from Helsefonden for this work [Grant No. 23-B-0188]. TMO has received a speaker fee from Lundbeck A/S for unrelated work. The remaining authors have no disclosure to declare. Data and code availability The register data for this study is stored on a secure server at Statistic Denmark. Due to Danish legislation, microdata kept on the server cannot be shared for disclosure. 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J Child Psychol Psychiatry 48(3–4):245–261. 10.1111/j.1469-7610.2006.01714.x Zijlmans MA, Riksen-Walraven JM, de Weerth C (2015) Associations between maternal prenatal cortisol concentrations and child outcomes: A systematic review. Neurosci Biobehav Rev 53:1–24. 10.1016/j.neubiorev.2015.02.015 Sahu MK et al (2022) A systematic review and meta-analysis of serum and plasma cortisol levels in depressed patients versus control. Indian J Psychiatry 64(5):440–448. 10.4103/indianjpsychiatry.indianjpsychiatry_561_21 Nandam LS et al (2019) Cortisol and Major Depressive Disorder-Translating Findings From Humans to Animal Models and Back. Front Psychiatry 10:974. 10.3389/fpsyt.2019.00974 Sarkar P et al (2008) Maternal antenatal anxiety and amniotic fluid cortisol and testosterone: possible implications for foetal programming. J Neuroendocrinol 20(4):489–496. 10.1111/j.1365-2826.2008.01659.x Jacovides C et al (2024) Association of Pregnant Women's Perinatal Depression with Sociodemographic, Anthropometric and Lifestyle Factors and Perinatal and Postnatal Outcomes: A Cross-Sectional Study. J Clin Med 13(7). 10.3390/jcm13072096 Wu V et al (2019) Associations Among Mothers' Depression, Emotional and Learning-Material Support to Their Child, and Children's Cognitive Functioning: A 16-Year Longitudinal Study. Child Dev 90(6):1952–1968. 10.1111/cdev.13071 Martucci M et al (2021) The mother-baby bond: a systematic review about perinatal depression and child developmental disorders. Riv Psichiatr 56(5):223–236. 10.1708/3681.36670 Hay DF et al (2008) Antepartum and postpartum exposure to maternal depression: different effects on different adolescent outcomes. J Child Psychol Psychiatry 49(10):1079–1088. 10.1111/j.1469-7610.2008.01959.x Faleschini S et al (2019) Associations of Prenatal and Postnatal Maternal Depressive Symptoms with Offspring Cognition and Behavior in Mid-Childhood: A Prospective Cohort Study. Int J Environ Res Public Health 16(6). 10.3390/ijerph16061007 van der Waerden J et al (2017) Persistent maternal depressive symptoms trajectories influence children's IQ: The EDEN mother-child cohort. Depress Anxiety 34(2):105–117. 10.1002/da.22552 Cortes Hidalgo AP et al (2020) Prenatal Maternal Stress and Child IQ. Child Dev 91(2):347–365. 10.1111/cdev.13177 Plomin R, Deary IJ (2015) Genetics and intelligence differences: five special findings. Mol Psychiatry 20(1):98–108. 10.1038/mp.2014.105 Galler JR et al (2004) Postpartum maternal moods and infant size predict performance on a national high school entrance examination. J Child Psychol Psychiatry 45(6):1064–1075. 10.1111/j.1469-7610.2004.t01-1-00299.x Murray L et al (2010) The effects of maternal postnatal depression and child sex on academic performance at age 16 years: a developmental approach. J Child Psychol Psychiatry 51(10):1150–1159. 10.1111/j.1469-7610.2010.02259.x Schmidt M, Pedersen L, Sørensen HT (2014) The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 29(8):541–549. 10.1007/s10654-014-9930-3 Christensen GT et al (2018) Data Resource Profile: Danish Conscription Registry Data (DCRD). Int J Epidemiol, 47(4): pp. 1023-1024e. 10.1093/ije/dyy048 Bliddal M et al (2018) The Danish Medical Birth Register. Eur J Epidemiol 33(1):27–36. 10.1007/s10654-018-0356-1 Schmidt M et al (2015) The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol 7:449–490. 10.2147/clep.S91125 Mors O, Perto GP, Mortensen PB (2011) The Danish Psychiatric Central Research Register. Scand J Public Health 39(7 Suppl):54–57. 10.1177/1403494810395825 Baadsgaard M, Quitzau J (2011) Danish registers on personal income and transfer payments. Scand J Public Health 39(7 Suppl):103–105. 10.1177/1403494811405098 Jensen VM, Rasmussen AW (2011) Danish Education Registers. Scand J Public Health 39(7 Suppl):91–94. 10.1177/1403494810394715 Teasdale TW (2009) The Danish draft board's intelligence test, Børge Priens Prøve: psychometric properties and research applications through 50 years. Scand J Psychol 50(6):633–638. 10.1111/j.1467-9450.2009.00789.x Teasdale TW et al (2011) The reliability and validity of the Danish Draft Board Cognitive Ability Test: Børge Prien's Prøve. Scand J Psychol 52(2):126–130. 10.1111/j.1467-9450.2010.00862.x Mortensen EL, Reinisch JM, Teasdale TW (1999) Intelligence as measured by the WAIS and a military draft board group test. Scand J Psychol 31:315–318 Charlson ME et al (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383. 10.1016/0021-9681(87)90171-8 Quan H et al (2011) Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 173(6):676–682. 10.1093/aje/kwq433 Austin PC (2009) Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med 28(25):3083–3107. 10.1002/sim.3697 Kessing LV et al (2023) Lifetime Incidence of Treated Mental Health Disorders and Psychotropic Drug Prescriptions and Associated Socioeconomic Functioning. JAMA Psychiatry 80(10):1000–1008. 10.1001/jamapsychiatry.2023.2206 Pottegård A et al (2017) Data Resource Profile: The Danish National Prescription Registry. Int J Epidemiol 46(3):798–798. 10.1093/ije/dyw213 Hafer RW (2016) New Estimates on the Relationship between IQ, Economic Growth and Welfare SSRN Electron J., Published online O'Connor TG et al (2014) Diurnal cortisol patterns and psychiatric symptoms in pregnancy: short-term longitudinal study. Biol Psychol 96:35–41. 10.1016/j.biopsycho.2013.11.002 Osborne S et al (2018) Corrigendum to Antenatal depression programs cortisol stress reactivity in offspring through increased maternal inflammation and cortisol in pregnancy: The Psychiatry Research and Motherhood - Depression (PRAM-D) study [Psychoneuroendocrinology 98 () 211–221]. Psychoneuroendocrinology, 2020. 119: p. 104795. 10.1016/j.psyneuen.2020.104795 O'Donnell KJ et al (2012) Maternal prenatal anxiety and downregulation of placental 11β-HSD2. Psychoneuroendocrinology 37(6):818–826. 10.1016/j.psyneuen.2011.09.014 Burcusa SL, Iacono WG (2007) Risk for recurrence in depression. Clin Psychol Rev 27(8):959–985. 10.1016/j.cpr.2007.02.005 Spijker J et al (2002) Duration of major depressive episodes in the general population: results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Br J Psychiatry 181:208–213. 10.1192/bjp.181.3.208 Ashraf S et al (2023) Impact of Paternal Depression on Child Neurodevelopmental Outcomes and Disorders. Prim Care Companion CNS Disord 25(1). 10.4088/PCC.22r03303 Rahbari N et al (2024) The longitudinal impact of pre- and postnatal maternal depression and anxiety on children's cognitive and language development. Dev Psychol 60(4):764–777. 10.1037/dev0001700 Ahun MN et al (2021) Sex differences in the association between maternal depression and child and adolescent cognitive development: a systematic review and meta-analysis. Psychol Med 51(9):1431–1440. 10.1017/s0033291721001689 Additional Declarations Competing interest reported. MB and TGP have received salary from Helsefonden hfor this work [Grant No. 23-B-0188]. TMO has received a speaker fee from Lundbeck A/S for unrelated work. The remaining authors have no disclosure to declare. Supplementary Files Supplementary.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 15 Mar, 2026 Reviews received at journal 23 Feb, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers agreed at journal 02 Feb, 2026 Reviews received at journal 14 Sep, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviewers invited by journal 17 Aug, 2025 Editor assigned by journal 01 Apr, 2025 Submission checks completed at journal 20 Mar, 2025 First submitted to journal 18 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6252560","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":502650002,"identity":"ce8a9e97-2263-469f-97c2-60275bf57168","order_by":0,"name":"Tanja Gram Petersen","email":"data:image/png;base64,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","orcid":"","institution":"University of Southern Denmark","correspondingAuthor":true,"prefix":"","firstName":"Tanja","middleName":"Gram","lastName":"Petersen","suffix":""},{"id":502650003,"identity":"2dd887e2-a0c0-4095-bb5b-b2845b766014","order_by":1,"name":"Rikke Wesselhoeft","email":"","orcid":"","institution":"University of Southern Denmark","correspondingAuthor":false,"prefix":"","firstName":"Rikke","middleName":"","lastName":"Wesselhoeft","suffix":""},{"id":502650004,"identity":"85a6cd03-2ca7-4c4c-bcc2-7e4c6c68a816","order_by":2,"name":"Gunhild Tidemann Okholm","email":"","orcid":"","institution":"University of Southern Denmark","correspondingAuthor":false,"prefix":"","firstName":"Gunhild","middleName":"Tidemann","lastName":"Okholm","suffix":""},{"id":502650005,"identity":"2c16ec22-e222-41ed-8f75-f31ff9c0dab9","order_by":3,"name":"Trine Munk-Olsen","email":"","orcid":"","institution":"Region of Southern Denmark","correspondingAuthor":false,"prefix":"","firstName":"Trine","middleName":"","lastName":"Munk-Olsen","suffix":""},{"id":502650006,"identity":"e6baba3e-4391-4e24-b8fa-3bb95abf4c61","order_by":4,"name":"Merete Osler","email":"","orcid":"","institution":"Bispebjerg and Frederiksberg Hospitals The Capital Region","correspondingAuthor":false,"prefix":"","firstName":"Merete","middleName":"","lastName":"Osler","suffix":""},{"id":502650007,"identity":"35fb663d-f28d-466d-82e2-e150e441d7b1","order_by":5,"name":"Lars Meinertz Byg","email":"","orcid":"","institution":"University of Newcastle","correspondingAuthor":false,"prefix":"","firstName":"Lars","middleName":"Meinertz","lastName":"Byg","suffix":""},{"id":502650008,"identity":"080defc7-3e3e-48b3-aa6a-ccb229d1892c","order_by":6,"name":"Veerle Bergink","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Veerle","middleName":"","lastName":"Bergink","suffix":""},{"id":502650009,"identity":"21921536-7558-44da-8ee0-7434e44948d7","order_by":7,"name":"Kirstine Agnete Davidsen","email":"","orcid":"","institution":"Region of Southern Denmark","correspondingAuthor":false,"prefix":"","firstName":"Kirstine","middleName":"Agnete","lastName":"Davidsen","suffix":""},{"id":502650010,"identity":"e9bf3261-c8d0-42d9-8157-5296ac245a58","order_by":8,"name":"Mette Bliddal","email":"","orcid":"","institution":"University of Southern Denmark","correspondingAuthor":false,"prefix":"","firstName":"Mette","middleName":"","lastName":"Bliddal","suffix":""}],"badges":[],"createdAt":"2025-03-18 11:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6252560/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6252560/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89824118,"identity":"5107a747-4863-4e0b-a0c3-38519b2ba579","added_by":"auto","created_at":"2025-08-25 12:15:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":219734,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of the study population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnly a few are exempt from conscription a priori. Postponement for e.g. educational reasons may explain the relatively high non-attendance rate between 2014 and 2019, especially for the latest birth cohorts.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6252560/v1/3f4d8e2b85e9df7b29626ff3.png"},{"id":89824117,"identity":"29b9f717-77fc-4ee6-8ad2-2502518adb62","added_by":"auto","created_at":"2025-08-25 12:15:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":173060,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCognitive test score (Børge Priens Prøve) according to maternal and paternal emotional disorders\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSD: standard deviation, No.: number, 95% CI: 95% confidence interval\u003c/p\u003e\n\u003cp\u003eMean differences in SD was estimated using linear regression. The adjusted model included an Inverse probability weight (IPW). When assessing maternal exposure, the IPW was computed as the inverse of being exposed given maternal age (included as restricted cubic splines), cohabitation status, primiparity, birth year of the child, family income, highest maternal educational degree, maternal occupational status, maternal Charlson Comorbidity Index, and other maternal psychiatric history. When assessing paternal exposure, the IPW was computed as the inverse of being exposed given paternal age (included as restricted cubic splines), cohabitation status, primiparity, birth year of the child, family income, highest paternal educational degree, paternal occupational status, paternal Charlson Comorbidity Index, and other paternal psychiatric history.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6252560/v1/7a15b6c08c17073b439fa7d5.png"},{"id":89825520,"identity":"7de0fddd-2766-4595-91e0-5d9c0d538da8","added_by":"auto","created_at":"2025-08-25 12:31:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1708629,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6252560/v1/97e23e39-5a61-4dca-b2e5-e4244edcd42b.pdf"},{"id":89824119,"identity":"6d1989e6-1182-4b0b-9b97-6be27c9a8a6c","added_by":"auto","created_at":"2025-08-25 12:15:23","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":34562,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-6252560/v1/feac768dc897218a8756bec8.docx"}],"financialInterests":"Competing interest reported. MB and TGP have received salary from Helsefonden hfor this work [Grant No. 23-B-0188]. TMO has received a speaker fee from Lundbeck A/S for unrelated work. The remaining authors have no disclosure to declare.","formattedTitle":"Maternal anxiety or depression and cognitive ability in young male offspring: A population-based cohort study using cognitive test scores from the Danish Conscription Board Examination","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnxiety and depressive disorders, onward named emotional disorders, are common among women during the reproductive years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The perinatal period, which encompasses pregnancy and the first year following delivery, is particularly associated with a high prevalence of emotional disorders, including postpartum depression. Up to one in four women will experience anxiety or depression during this time [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and for many, the symptoms persist throughout the offspring\u0026rsquo;s early childhood [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Emerging research suggests that maternal emotional disorders negatively affect various child developmental outcomes, including cognitive ability [\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe prenatal period is crucial for the brain development. Maternal emotional disorders during this period may adversely influence fetal brain development, and potentially impact later cognitive ability [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These effects may result from hormonal changes, such as elevated cortisol levels [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], and from suboptimal lifestyle factors [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which can compromise the intrauterine environment and potentially impair long-term cognitive development [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, genetics and the postnatal familial environment, including parenting quality, play significant roles in linking maternal emotional disorders and child cognition [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Although the timing of maternal emotional disorders is considered important, it is unclear at what time maternal emotional disorders exert the greatest influence on offspring cognitive ability and whether in-utero exposure increase vulnerability. Observational studies on the timing of maternal emotional disorders and offspring cognitive ability, measured by IQ, have produced inconsistent findings: some suggest that prenatal influences increase vulnerability [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], while others do not [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Most previous studies focus on cognitive outcomes in childhood only [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], but follow-up and assessment in youth/adulthood may better represent the life-course impact on cognitive ability since the genetic impact on IQ becomes more pronounced with advancing age [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Only a few studies have examined maternal emotional disorders in relation to offspring cognitive ability while following the offspring until adolescence [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. All of these studies rely on relatively small sample sizes. Moreover, most use maternal symptom reports, which include non-severe or non-clinical conditions of emotional disorders, and do not assess prenatal exposure.\u003c/p\u003e\u003cp\u003eTo address the evidence-gab, we aimed to examine how the timing of incident psychiatric diagnosis of maternal emotional disorders is associated with male offspring's cognitive ability in early adulthood in Danish conscripts, which represent a large population-based cohort. Our priori hypothesis was that children born to mothers with anxiety or depression during pregnancy would show a more pronounced association compared to mothers diagnosed after the child was born due to a potentially increased vulnerability with in-utero exposure.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eIn Denmark, all young adult men are legally required to undergo assessments to determine their suitability for military service, including a cognitive test - at the Danish Conscription Board Examination. Furthermore, the nationwide Danish Patient Registry holds information on hospital diagnoses on the mothers of conscripts. Using these data, we conducted a population-based cohort study on males born in Denmark during 1996\u0026ndash;2001 to examine the association between maternal emotional disorders before, during, or after pregnancy and offspring cognitive ability, along exploring paternal influences as a negative control analysis.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData sources\u003c/h2\u003e\u003cp\u003eAll residents in Denmark are assigned a unique personal identification number, which enables the linkage on an individual level of various registers [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. We derived data from the following Danish nationwide registers: The Danish Conscription Registry which maintains information on the examinations for military recruitment [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The registry includes data on all males in Denmark, excluding those with documented conditions such as epilepsy, type I diabetes, intellectual disabilities, severe psychiatric illness, and other conditions, which, a priori, disqualify them from military service [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The Danish Medical Birth Register (the Birth Register) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], which enables linkage to biological parents and holds pregnancy- and birth-related information, including date of birth and gestational age. The Danish National Patient Registry (the Patient Register), which contains information on all inpatient hospital contacts since 1977 and outpatient hospital contacts since 1995. It informed on the date of hospital contact and diagnoses coded according to the International Classification of Diseases, version 8 (ICD-8) until 1994 and version 10 (ICD-10) from 1995 onward [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. We also employed the Danish Psychiatric Central Research Register (the Psychiatric Register) to derive data on psychiatric hospital contacts prior to 1995 with diagnoses coded according to ICD-8 [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The Danish Civil Registration System Register provided data on demographic factors [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], while socioeconomic registers at Statistics Denmark provided data on parental socioeconomic data [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eIn the Birth Register, sex is designated at birth and binary categorized (male/female). In this register, we identified all males (N\u0026thinsp;=\u0026thinsp;205,828) born in Denmark between January 1, 1996, and December 31, 2001 to form the study population. Males who died or immigrated before the age of 18 and those not assessed at the Conscription Board Examinations between January 1, 2014, and December 31, 2019 were excluded. We also excluded individuals with missing data on the Danish military cognitive test, with missing information necessary to calculate the pregnancy period, or with missing maternal baseline characteristics. The offspring constituted the study unit, and each mother could be included multiple times if she had more than one son represented in the study population. Seventeen percent of the mothers were represented with more than one son.\u003c/p\u003e\n\u003ch3\u003eExposure\u003c/h3\u003e\n\u003cp\u003eWe defined maternal emotional disorders by an in- or outpatient diagnosis of either an anxiety or a depressive disorder in the Patient Register or the Psychiatric Register. We included the following codes: Unipolar depressive disorders: F32-F33*(ICD10) and 296.09, 298.29, 300.49, 301.19 (ICD8) and anxiety disorders: F40-F48* (ICD10) and 300.x9 (minus 300.49), 305.x9, 305.68, 307.99 (ICD8).\u003c/p\u003e\u003cp\u003eThe timing of the incident maternal emotional disorder diagnosis was determined based on the date of the first (ever) hospital contact with a diagnosis of anxiety or depressive disorder. The timing was categorized into six groups: 1) no hospital contact, 2) before pregnancy, 3) during pregnancy, 4) within the first year after birth, 5) 1\u0026ndash;5 years after birth, and 6) 6\u0026ndash;17 years after birth. Data from the Birth Register was used to determine pregnancy periods, defined as the time from conception (calculated as the day of delivery minus gestational age) to delivery.\u003c/p\u003e\n\u003ch3\u003eOutcome\u003c/h3\u003e\n\u003cp\u003eThe outcome measure was cognitive ability assessed by the Danish military cognitive test, B\u0026oslash;rge Priens Pr\u0026oslash;ve (BPP). The BPP is a group-administered paper-and-pencil cognitive test used as an assessment tool to evaluate individuals' eligibility for military service in Denmark since the 1950s [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The BPP comprises four subtests assessing logical, verbal, numerical, and spatial reasoning abilities [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and it correlates (0.82) with the full-scale Wechsler Adult Intelligence Scale [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The total BPP score range from 0 to 78 and, for the outcome measure, we used the score per standard deviation (SD) derived from the study population. The total BPP-scores was obtained from the Danish Conscription Registry.\u003c/p\u003e\n\u003ch3\u003eCovariates\u003c/h3\u003e\n\u003cp\u003eBaseline was defined as the conception date of the pregnancy for each offspring under study.We derived information on birth year (1996\u0026ndash;1998, 1999\u0026ndash;2001) and primiparity (no, yes) for the index pregnancy from the Birth Register. Maternal age (\u0026le;\u0026thinsp;20, 21\u0026ndash;25, 26\u0026ndash;30, 31\u0026ndash;35, 36\u0026ndash;40, \u0026ge;\u0026thinsp;41 years) and maternal cohabitation status at baseline (single vs. living with a partner/married) were derived from the Danish Civil Registration System. The highest maternal educational degree at baseline (lower secondary, upper secondary, post-secondary) was obtained from Statistics Denmark. Additionally, we used data from Statistics Denmark the year prior to the baseline on family equivalent disposable income, categorized into tertiles for each baseline year, and maternal occupation (employed, unemployed/receiving social benefits, student). Furthermore, we defined comorbidity in mothers based on the Charlson Comorbidity Index (CCI) [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] with updated weights according to Quan 2011 [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. For this, we used primary and secondary hospital diagnosis codes (ICD8 and ICD10 codes) with a ten-year look-back period prior to baseline recorded in the Patient Register. The history of other maternal psychiatric disorders (no, yes) was identified through psychiatric hospital diagnoses (ICD10: F00-F31*, F34-F39*, F50-F99*(ICD10) and ICD8: 290\u0026ndash;315 (minus 296.09, 298.29, 300.49, 301.19, 300.x9, 305.x9, 305.68, 307.99)) from the Patient Register and psychiatric Register.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eBaseline characteristics were presented as frequencies for categorical and binary variables and as medians with interquartile-range for continuous variables. To assess baseline comparability between exposure groups, we computed standardized mean differences (SMD) using dummy-variables (no hospital contact vs. the different timing of incident diagnosis). The SMD compares the difference in means in units of the pooled standard deviation [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo balance differences in baseline characteristics between the exposure groups, we computed stabilized inverse probability weights (IPW). First, we used a multinomial logistic regression model, including the exposure variable of onset of maternal emotional disorder as the dependent variable, to determine the probability of exposure given baseline characteristics. The covariates were selected based on Directed Acyclic Graphs and included potential confounders: maternal age (included as restricted cubic splines), cohabitation status, primiparity, birth year of the child, family income, highest maternal educational degree, maternal occupational status, maternal CCI, and other maternal psychiatric history. Then, the IPW for each individual was calculated as the inverse of the probability of being exposed conditional on observed covariates. After applying the IPWs to the study population, the balance of baseline characteristics was evaluated, considering a SMD of less than 10% as acceptable [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e We used linear regression analysis to estimate the mean differences in the offspring cognitive test scores according to the timing of maternal incident emotional disorders. Normality was assessed through visual inspection and was not violated. IPW-adjusted estimates were presented with 95% confidence intervals (CIs), calculated using robust variance estimators to account for weights and sibling dependency. We performed a post hoc analysis to test trends in the primary results by including the categorized timing variables of the emotional disorders as a continuous variable in the regression model. We examined whether the association between the timing of maternal incident emotional disorders and mean offspring cognitive test score was modified by the child\u0026rsquo;s birth year, by conducting analyses stratified by birth years in the following two groups 1996\u0026ndash;1998 and 1999\u0026ndash;2001, and by testing the interaction term between exposure and birth year. We also examined the association after stratifying by parity and tested the interaction between exposure and parity.\u003c/p\u003e\u003cp\u003eTo assess the importance of the intrauterine environment, we employed a negative control model using fathers. This model examined the association between the timing of paternal incident emotional disorders and offspring cognitive test scores. We identified biological fathers through the Birth Register. If the fathers were not listed in this register, legal fathers at the time of birth were identified through the Danish Civil Registration System.\u003c/p\u003e\u003cp\u003eWe conducted a sensitivity analysis, adjusting the association between maternal emotional disorders and cognitive for paternal psychiatric history and paternal emotional disorders, and vice versa when paternal emotional disorders was the exposure.\u003c/p\u003e\u003cp\u003eFinally, we conducted a sensitivity analysis, adding information on filled prescriptions of antidepressants and anxiolytics (Anatomical Therapeutic Chemical (ATC) classification codes and N06A (antidepressants) and N05BA (anxiolytics)) to the exposure definition when assessing maternal emotional disorders and offspring cognitive test score. Most cases of emotional disorders are diagnosed and treated in general practice in Denmark and only the most severe cases are captured in the Danish National Patient Registry. Also, this approach account for any latency period from emotional disorder is first treated to a potential hospital diagnosis is registered [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In this analysis, the timing of incident maternal emotional disorder was determined by the date of first filled prescription or the date of the initial hospital diagnosis, whichever came first. Information on filled prescriptions was derived from the Danish National Prescription Registry, which contains data on all prescription drugs dispensed at outpatient pharmacies since 1995 and include date of dispensing and medications classified according to the ATC Classification System [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eData was analyzed using Stata BE 18.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eRegistration\u003c/h3\u003e\n\u003cp\u003eThe project was registered in OSF in July 2024 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.17605/OSF.IO/SV7W4\u003c/span\u003e\u003cspan address=\"10.17605/OSF.IO/SV7W4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eCharacteristics of the study population\u003c/h2\u003e\u003cp\u003eWe identified 205,828 males born in Denmark between 1996 and 2001. We excluded 7708 individuals who died or emigrated before the age of 18 years and 62,889 who did not attend the Conscription Board Examinations between 2014 and 2019, largely due to postponement. After also excluding 7605 with missing cognitive test scores (BPP) and 8239 with missing information on pregnancy periods or covariates, 119,387 men remained eligible and constituted the study population (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean age of the study population at the Conscription Board Examination was 18 years (SD\u0026thinsp;=\u0026thinsp;0.7).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWithin the cohort, 9959 mothers (8.3%) had had incident diagnosis of an emotional disorder at any time up to the child turned 18 years. Twelve percent (n\u0026thinsp;=\u0026thinsp;1233) of these were first (ever) diagnosed before pregnancy, 2.5% during pregnancy (n\u0026thinsp;=\u0026thinsp;251), and 4.8% within the first year postpartum (n\u0026thinsp;=\u0026thinsp;480). The prevalence of emotional disorders was higher among women who gave birth in 1999\u0026ndash;2001 compared to those who gave birth in 1996\u0026ndash;1998. Notably, a greater proportion of women in the later period were diagnosed before or during pregnancy compared to those in the earlier period (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMothers with emotional disorders were more likely to be primiparous compared to those without, except when the first diagnosis occurred during pregnancy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Mothers with emotional disorders were also younger, more often single, had lower family income and educational levels, were more frequently unemployed or receiving social benefits, and had a higher prevalence of comorbidities compared to mothers without such diagnoses. After applying the IPW, characteristics of the cohorts were similar with SMD below the 0.1 cutoff, although minor variation in baseline characteristics remained (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and online Table\u0026nbsp;2).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eAssociation between maternal emotional disorders and offspring cognitive test score\u003c/h2\u003e\u003cp\u003eThe mean cognitive test score was 40.9 (95% CI: 40.8; 40.9) in unexposed offspring. Maternal emotional disorders were associated with lower cognitive test scores regardless of the timing of diagnosis. The lowest mean cognitive test score was observed if the mother had an incident emotional disorder during pregnancy (mean cognitive test score 38.1, 95% CI: 37.1; 39.2). After adjustment, the mean cognitive test score of these offspring was 0.22 SD lower (-0.22 SD, 95% CI: -0.36; -0.08) than in offspring where the mother had no maternal emotional disorder (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The post hoc trend-analysis showed a statistically significant trend (p\u0026thinsp;\u0026lt;\u0026thinsp;0.000) when pre-pregnant\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics of the study population\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"8\" nameend=\"c9\" namest=\"c2\"\u003e\u003cp\u003eTiming of incident diagnosis of maternal emotional disorder\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo hospital contact\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;109,428\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBefore pregnancy\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;1233\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDuring pregnancy\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;251\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFirst year after birth\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;480\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1\u0026ndash;5 years after birth\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;2345\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6\u0026ndash;17 years after birth\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;5650\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSMD\u003c/p\u003e\u003cp\u003eraw\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSMD\u003c/p\u003e\u003cp\u003eIPW adjusted\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBirth year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.135\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.071\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1996-1998\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e65308 (92.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e532 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e137 (0.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e254 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1311 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3298 (4.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1999-2001\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e44120 (90.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e701 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e114 (0.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e226 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1034 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2352 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimiparity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e45381 (41.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e517 (41.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e101 (40.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e215 (44.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1059 (45.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2374 (42.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.047\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal age,\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003cp\u003e[Q1;Q3]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e29.0 [26.0;32.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e29.0\u003c/p\u003e\u003cp\u003e[24.0;33.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.0\u003c/p\u003e\u003cp\u003e[24.0;32.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e28.0 [25.0;32.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e27.0 [23.0;31.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e27.0 [23.0;30.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.032\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026le;20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3657 (3.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e92 (7.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21 (8.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e34 (7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e232 (9.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e594 (10.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21\u0026ndash;25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e22422 (20.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e285 (23.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e55 (21.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e116 (24.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e733 (31.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1668 (29.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u0026ndash;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e45843 (41.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e386 (31.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85 (33.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e168 (35.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e786 (33.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1995 (35.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e31\u0026ndash;35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e29408 (26.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e337 (27.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e64 (25.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e127 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e464 (19.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1108 (19.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e36\u0026ndash;40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7499 (6.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e124 (10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e23 (9.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e32 (6.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e125 (5.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e268 (4.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e599 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9 (0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (0.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5 (0.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e17 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot living with a partner/unmarried\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9561 (8.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e267 (21.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e66 (26.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e67 (14.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e419 (17.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e898 (15.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.202\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFamily income\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.199\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.054\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLow tertile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e35222 (32.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e615 (49.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e125 (49.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e170 (35.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1074 (45.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2716 (48.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMidle tertile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e37649 (34.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e352 (28.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e67 (26.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e172 (35.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e721 (30.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1719 (30.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHigh tertile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e36557 (33.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e266 (21.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e59 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e138 (28.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e550 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1215 (21.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal highest educational degree\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.074\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLower secondary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e23070 (21.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e531 (43.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94 (37.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e151 (31.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1014 (43.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2488 (44.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUpper secondary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e55015 (50.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e472 (38.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104 (41.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e218 (45.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e933 (39.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2282 (40.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePost-secondary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e31343 (28.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e230 (18.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53 (21.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e111 (23.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e398 (17.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e880 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnemployed/receiving\u003c/p\u003e\u003cp\u003esocial benefits\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20944 (19.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e495 (40.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e88 (35.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e125 (26.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e844 (36.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2179 (38.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.225\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.062\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCCI, \u0026ge;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e517 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e13 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e29 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e38 (0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.083\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther psychiatric historic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e431 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e307 (24.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19 (7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e18 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e71 (3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e107 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.341\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.164\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eSMD: Standardized mean differences, IPW: Inverse probability weighting, CCI: Charlson Comorbidity Index\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003csup\u003ea\u003c/sup\u003erow percentages\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003ediagnoses were excluded: The strongest association was observed for maternal emotional disorders during pregnancy, which weakened over time after birth.\u003c/p\u003e\u003cp\u003eWe observed the same patterns in the analyses stratified by birth cohort as in the primary analyses, except emotional disorders diagnosed within the first year postpartum were not associated with change in offspring cognitive test score in the birth cohort 1999\u0026ndash;2001 (-0.01 SD, 95% CI: -0.15;0.12) (p-value for interaction\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (online Table\u0026nbsp;3). When stratified by parity, the association was strongest for exposure during gestation in both primiparous and multiparous. Maternal diagnoses in the first postpartum year were not associated with offspring cognitive test scores among multiparous mothers (online Table\u0026nbsp;4), but the interaction was statistically insignificant. Overall, the estimates were less precise in the stratified analyses than in the primary analyses due to the smaller sample sizes and reduced statistical power.\u003c/p\u003e\u003cp\u003eAdditional adjustment for paternal emotional disorders and paternal history of other psychiatric disorders did not change the estimates for the association between maternal emotional disorders and offspring cognitive test score (online Table\u0026nbsp;5). When expanding the definition of maternal emotional disorders to also include filled prescription of antidepressants or anxiolytics, more mothers were classified as incident cases of emotional disorders (n\u0026thinsp;=\u0026thinsp;43,554), (online Table\u0026nbsp;6). The adjusted mean differences remained comparable to the main analysis, but no stronger association was observed for the pregnancy period.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eAssociation between paternal emotional disorders and offspring cognitive test score\u003c/h2\u003e\u003cp\u003eWe included 115,526 offspring with complete paternal information on covariates in the negative control analysis using paternal emotional disorders as the exposure (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Five percent (n\u0026thinsp;=\u0026thinsp;6112) of the fathers were diagnosed with emotional disorders before their child turned 18 years old. Offspring exposed to paternal emotional disorders had lower mean cognitive test scores compared to unexposed, with consistent strengths of association regardless of the timing. Adjusted mean differences per SD ranged from \u0026minus;\u0026thinsp;0.14 (95% CI: -0.23;-0.04) before pregnancy to -0.18 (95% CI: -0.22;-0.15) 6\u0026ndash;17 years after the child was born birth (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Additional adjustment for maternal emotional disorders and maternal psychiatric history did not affect the estimates (online Table\u0026nbsp;7).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this large population-based sample, we find that maternal emotional disorders are associated with male offspring cognitive ability in early adulthood, as measured by the Danish military cognitive test (Danish: \u0026ldquo;B\u0026oslash;rge Priens Pr\u0026oslash;ve\u0026rdquo;). The association was present regardless of the time of onset, but it was strongest when maternal emotional disorders were diagnosed during pregnancy, although this estimate also showed the greatest statistical imprecision. Likewise and noteworthy, paternal emotional disorders were also associated with offspring cognitive ability - with consistent strength across different time points for exposure.\u003c/p\u003e\u003cp\u003eIn absolute terms, the difference in cognitive test score (ranging from 0 to 78) was 2.7 points between offspring unexposed to maternal emotional disorder and those exposed during pregnancy. While these effect sizes are relatively small and may not be clinically relevant for the individual, the potential population-level impact of reducing the diagnostic burden may remain important, given the influence of cognitive ability on life outcomes such as socioeconomic or educational outcomes [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe hypothesized a stronger association with emotional disorders diagnosed during pregnancy compared to other time periods due to a potential increased vulnerability with in-utero exposure. One proposed mechanism is that severe anxiety and depression interfere through altered cortisol levels [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] with fetal brain development, potentially impacting later cognitive ability [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Specifically, elevated maternal cortisol levels can reduce the activity of the placental enzyme 11β-HSD2, which converts cortisol to inactive cortisone, exposing the fetus to harmful levels of glucocorticoid signaling [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Alternative mechanisms include unhealthy lifestyle choices associated with perinatal depression [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Such choices could - independent of cortisol - adversely affect the intrauterine environment, potentially impacting the child's long-term cognitive development [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Our observation of the strongest association with maternal exposure during pregnancy, coupled with the absence of a similar finding for paternal exposure during the same period, provides a subtle signal of increased vulnerability in offspring exposed in utero. Additionally, emotional disorders tend to be recurrent and for up to 20\u0026ndash;30% of patients it develops into a chronic condition [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], and the significant test for trend with maternal emotional disorders could hint an accumulating effect, due to longer exposure duration. Regardless, the effect estimate for exposure diagnoses during pregnancy should be interpreted with caution due to the statistical uncertainty.\u003c/p\u003e\u003cp\u003eIn our study, paternal and maternal emotional disorders during the offspring\u0026rsquo;s childhood had comparable associations with cognitive ability in the offspring at age 18 years. Parental emotional disorders are associated with genetic factors and postnatal familial influences, which are difficult to segregate and important factors influencing offspring neurodevelopment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. For example, evidence has demonstrated that mothers with depression more often have reduced mental resources for childcare and exhibit more negative emotions compared to mothers without depression [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Disregarding a maternal or paternal origin, reduced parent-infant interactions could adversely affect child development postpartum and the subsequent cognitive ability [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe existing evidence regarding the timing of maternal emotional disorders and cognitive ability remains inconclusive [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Some studies suggest that the prenatal period may be more sensitive than the postnatal period [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. This was suggested in the Avon Longitudinal Study, but the association between maternal self-reported depression and child IQ weakened and became statistically imprecise after adjusting for multiple confounders [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Our study found only a weak hint of a sensitive period for prenatal exposure. In contrast to our findings, others have found a stronger association with postnatal exposure when assessing cognitive outcomes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Overall, there is a notable lack of studies with repeated measurements to investigate developmental trajectories and critical periods, and many studies fail to control for all known confounders or are based on small sample sizes.\u003c/p\u003e\u003cp\u003eA key strength of our study is the use of a large, population-based cohort followed to adulthood, offering a more comprehensive view of life-course impacts on cognitive ability than childhood-only assessments. The Conscription Board Examination is mandatory for Danish males. Only a few are exempt from conscription a priori, such as those with severe somatic or psychiatric conditions. Postponement for educational reasons may primarily explain the relatively high non-attendance rate between 2014 and 2019, particularly among the latest birth cohorts, where the associations between pre- and postnatal influences and offspring cognitive ability were attenuated. Another strength is the use of a standardized cognitive measure, the B\u0026oslash;rge Priens Pr\u0026oslash;ve (BPP), which correlates with the Wechsler Adult Intelligence Scale [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], ensuring reliable and valid cognitive measurements. Finally, a key advantage is the inclusion of fathers in a negative control model, which helps separate in utero exposure from genetic and environmental influences.\u003c/p\u003e\u003cp\u003eOur study also has limitations. First, females were not included in the study because military service is voluntary for females, resulting in a non-representative sample of women. Thus, our findings are generalizable only to male offspring. Additionally, there is a potential misclassification of the exposure, as anxiety and depression are often underdiagnosed if only hospital records are used [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] and onset may be misestimated due to the latency between symptoms and the psychiatric diagnosis. To address this, we used filled prescriptions for anxiety/depression medication as a proxy for emotional disorders in a sensitivity analysis. The absence of a stronger association for emotional disorders during pregnancy compared to other periods may suggest antenatal vulnerability only emerges with severe disorders or that psychopharmacology mitigates fetal impact. Furthermore, the analytic choice of using \u0026ldquo;incident diagnosis\u0026rdquo; classified six mothers with records of hospital diagnoses during pregnancy as having the disorder \u0026ldquo;before pregnancy\u0026rdquo;, which can have resulted in a dilution of the association for the pregnancy period. Finally despite adjusting for various confounders, it is important to consider that poorly measured or unmeasured factors, such as maternal IQ and psychosocial stressors, may have influenced the associations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis large population-based cohort study shows a moderate association between maternal emotional disorders and male offspring's cognitive ability at age 18 years. The association of paternal emotional disorders largely resampled the association found for maternal disorders. While the findings should be interpreted with caution, we observed a weak indication of a sensitive period for maternal disorders during pregnancy, with no comparable pattern for paternal emotional disorders. The cognitive differences observed in this study are small and unlikely to be clinically relevant, but they may have broader implications at the population level. We encourage similar studies in other cohorts and the inclusion of female offspring.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthical approval\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe manuscript does not contain clinical studies or patient data. By Danish law, studies based solely on register data do not require ethical approval and data from the Danish national registers can be used for research proposes without informed consent from participants. This study was performed in line with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by Helsefonden [Grant No. 23-B-0188].\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interests\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eMB and TGP have received salary from Helsefonden for this work [Grant No. 23-B-0188]. TMO has received a speaker fee from Lundbeck A/S for unrelated work. The remaining authors have no disclosure to declare.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eData and code availability\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe register data for this study is stored on a secure server at Statistic Denmark. Due to Danish legislation, microdata kept on the server cannot be shared for disclosure. Aggregated data (results) and do-files can be extracted and shared upon request by emailing the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors’ contribution\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eTGP and MB conceptualized the study. TGP compiled the analysis plan and performed the data management, and statistical analyses and wrote the original draft with input from MB. MB, RW, GTO, TMO, MO, LMB VB, and KD contributed to the analysis plan and/or post hoc analyses, and reviewed and edited the manuscript. All authors are ultimately responsible for deciding to submit the study for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBeck C et al (2024) A comprehensive analysis of age of onset and cumulative incidence of mental disorders: A Danish register study. 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Psychol Med 51(9):1431\u0026ndash;1440. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/s0033291721001689\u003c/span\u003e\u003cspan address=\"10.1017/s0033291721001689\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"social-psychiatry-and-psychiatric-epidemiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sppe","sideBox":"Learn more about [Social Psychiatry and Psychiatric Epidemiology](http://link.springer.com/journal/127)","snPcode":"127","submissionUrl":"https://submission.nature.com/new-submission/127/3","title":"Social Psychiatry and Psychiatric Epidemiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Depression, anxiety, cognition, intrauterine exposure, pregnancy, maternal health","lastPublishedDoi":"10.21203/rs.3.rs-6252560/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6252560/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe aimed to study how the timing of incident maternal emotional disorders is associated with male offspring's cognitive ability in early adulthood using cognitive test data from military conscription in a population-based cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe linked all males (conscripts) born in Denmark 1996–2001 to parental hospital records to identify anxiety or depression (emotional disorders). Linear regression assessed the association between the timing of the first maternal diagnosis (before, during, or after birth (0–1, 1–5, 6–17 years)) and cognitive ability measured at the Danish Conscription Board Examination 2014–2019. Paternal emotional disorders served as negative controls to differentiate maternal pregnancy exposures from genetic and postnatal influences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study included 119,387 males, with 9,959 (8.3%) having mothers diagnosed with emotional disorders. Offspring exposed to maternal emotional disorders had lower cognitive test scores (ranging from − 0.22 to -0.10 standard deviations (SD) lower than unexposed) at mean age 18, particularly if the mother was diagnosed during pregnancy (-0.22 SD, 95% CI: -0.36; -0.08). Paternal emotional disorders were also linked to a lower cognitive test score, but showed more consistent associations across all time points (-0.18 to -0.14 SD lower than unexposed).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMaternal emotional disorders were overall associated with male offspring's long-term cognitive ability. Paternal disorders showed similar associations. While the findings require cautious interpretation, the findings suggest a weak signal of a window of sensitivity for maternal disorders during gestation, with no equivalent signal for paternal disorders. We encourage similar studies with female offspring.\u003c/p\u003e","manuscriptTitle":"Maternal anxiety or depression and cognitive ability in young male offspring: A population-based cohort study using cognitive test scores from the Danish Conscription Board Examination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-25 12:15:18","doi":"10.21203/rs.3.rs-6252560/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-15T19:11:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-23T16:32:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7447601267739155028792792275235915918","date":"2026-02-20T07:08:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230593011915516870103397114014403568044","date":"2026-02-18T13:13:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"188935984336628580589449373352546825071","date":"2026-02-02T06:32:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-15T02:44:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9903263941226991865097257160375351243","date":"2025-08-17T17:40:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-17T10:19:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-01T10:49:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-20T11:08:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Social Psychiatry and Psychiatric Epidemiology","date":"2025-03-18T11:09:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"social-psychiatry-and-psychiatric-epidemiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sppe","sideBox":"Learn more about [Social Psychiatry and Psychiatric Epidemiology](http://link.springer.com/journal/127)","snPcode":"127","submissionUrl":"https://submission.nature.com/new-submission/127/3","title":"Social Psychiatry and Psychiatric Epidemiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f4163e04-5f33-4d62-80b1-66a38a74ae21","owner":[],"postedDate":"August 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-27T13:00:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-25 12:15:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6252560","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6252560","identity":"rs-6252560","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}