Preterm birth, poor foetal growth and anxiety disorders in a Finnish nationwide register sample.

AIM: We examined the associations between preterm birth, poor foetal growth and anxiety disorders among children and adolescents. Additionally, we examined the impact of common comorbidities and specific anxiety disorders separately. METHODS: Three Finnish registers provided data on a nationwide birth cohort of 22,181 cases with anxiety disorders and 74,726 controls. Conditional logistic regression was used to examine the associations. RESULTS: Extremely very preterm birth and moderate-late preterm birth were associated with increased adjusted odds ratios (aOR) for anxiety disorders (aOR 1.39, 95% CI 1.11-1.75 and aOR 1.13, 95% CI 1.03-1.23, respectively). Weight for gestational age of less than -2SD (aOR 1.29, 95% CI 1.17-1.42) and -2SD to -1SD (aOR 1.08, 95% CI 1.03-1.14) were associated with increased odds ratios for anxiety disorders. When comorbidities were considered, the associations became statistically insignificant for pure anxiety disorders, but remained significant in the groups with comorbid depressive or neurodevelopmental disorders. CONCLUSION: Preterm birth and poor foetal growth increased the odds for anxiety disorders. However, the associations seem to be explained by the conditions of comorbid depressive and neurodevelopmental disorders. Comorbidities should be considered when examining and treating child and adolescent anxiety disorders.

Perinatal risk factors and reactive attachment disorder: A nationwide population-based study.

AIM: To examine the association between several perinatal and obstetric risk factors and reactive attachment disorder in children diagnosed in specialised services. METHODS: In this nested case-control study, 614 cases with reactive attachment disorder and 2423 controls matched with age and sex were identified from Finnish national registers. Conditional logistic regression was used to examine the association between a number of perinatal risk factors and reactive attachment disorder. RESULTS: In the adjusted analysis, a low birthweight of <2500 g was associated with an increased odds of reactive attachment disorder, with an odds ratio (OR) of 1.96 and 95% confidence interval (CI) of 1.17, 3.30 and a birthweight of 4000-4499 grams was associated with decreased odds OR 0.49 (95% CI 0.31, 0.75). The odds for being diagnosed with reactive attachment disorder increased with a gestational age of <32 weeks OR 3.72 (95% CI 1.52, 9.10), induced labour OR 1.34 (95% CI 1.03, 1.75) and monitoring in a neonatal intensive care unit (NICU) OR 1.67 (95% CI 1.09, 2.55). CONCLUSION: We found associations between low birthweight, preterm birth, NICU admission and reactive attachment disorder. The findings add to the current literature on the understanding of the development of reactive attachment disorder in children.

Maternal serum C-reactive protein (CRP) and offspring attention deficit hyperactivity disorder (ADHD).

Exposure to infection and inflammation during the fetal period are associated with offspring neuropsychiatric disorders. Few previous studies have examined this association with ADHD with mixed findings. This study aims to examine the association between early gestational maternal C-reactive protein (CRP), prospectively assayed in stored maternal sera and the risk of ADHD in offspring. This study is based on the Finnish Prenatal studies of ADHD (FIPS-ADHD) with a nested case-control design. It includes all singleton-born children in Finland between January 1, 1998 and December 31, 1999 and diagnosed with ADHD. A total of 1079 cases and equal number of controls were matched on date of birth, sex and place of birth. Maternal CRP levels were assessed using a latex immunoassay from archived maternal serum specimens, collected during the first and early second trimester of pregnancy. Elevated maternal CRP when analyzed as a continuous variable was not associated with offspring ADHD (OR 1.05, 95% CI 0.96-1.15). No significant associations were seen in the highest quintile of CRP (OR 1.18, 95% CI 0.88-1.58). The results were similar in both sexes as well as among ADHD cases with or without comorbid ASD or conduct disorder. In this first study examining CRP, a biomarker for inflammation, during early pregnancy in relation to offspring ADHD, we report no significant associations. The lack of any association, when considered with positive findings seen in ASD and schizophrenia, and negative findings in bipolar disorder suggests different pathways linking maternal immune activation and development of various neuropsychiatric disorders.

Social risk factors for speech, scholastic and coordination disorders: a nationwide register-based study.

BACKGROUND: Broadly defined learning and coordination disorders (LCDs) are common in the population and have previously been associated with familial social risk factors and male sex. However, comprehensive nationwide studies of these risk factors in LCD subgroups are lacking. Our objective was to assess different LCDs in relation to sex and maternal education, marital status and socioeconomic status based on occupation. METHODS: We conducted a nationwide register-based study. The following diagnoses were identified from the Finnish Hospital Discharge Register (FHDR) according to the ICD-10 (n = 28,192): speech disorders (F80), scholastic disorders (F81), motor and coordination disorders (F82) and mixed developmental disorder (F83). To study cumulative incidence and male: female ratios of service use of LCDs, we used a cohort design among all Finnish children born singleton 1996-2007 (n = 690,654); to study social risk factors, we used a nested case-control design with extensive register data on both cases and matched controls (n = 106,616). RESULTS: The cumulative incidence was 4.7% for any LCD by age 15 and the changes in cumulative incidence over time were minor. The male: female ratios were 2.2-3.0 across LCD subgroups. Learning and coordination disorders were more common in households with lower maternal education, socioeconomic status based on occupation and among children with single mothers at the time of birth; the odds ratios (OR) for any LCD were 1.2-1.9 across risk factors. The odds for LCD diagnosis increased linearly with the number of social risk factors, except for coordination disorder. The effect size of three risk factors was highest in the group with mixed or multiple LCDs; OR 3.76 (95% CI 3.31-4.28). CONCLUSIONS: Multiple social risk factors increase the odds for multiple, more comprehensive learning difficulties. The findings have implications for service planning, as early identification and interventions of learning and coordination disorders might reduce related long-term social adversities.

Lower Apgar scores and Caesarean sections are related to attention-deficit/hyperactivity disorder.

AIM: We examined the associations between prenatal, birth-related and newborn risk factors and attention-deficit/hyperactivity disorder (ADHD). METHODS: In this population-based study, 10 409 subjects diagnosed with ADHD by 31 December 2011 and 39 124 controls, born between 1 January 1991 and 31 December 2005, were identified from Finnish nationwide registers. Perinatal data were obtained from the Birth Register. Conditional logistic regression was used to examine the associations after controlling for confounders. RESULTS: Lower Apgar scores were associated with a higher risk of ADHD, with odds ratios of 1.12 (95% confidence intervals 1.06-1.19) for one-minute Apgar scores of 7-8, 1.17 (95% CI 1.02-1.35) for scores of 5-6 and 1.41 (95% CI 1.18-1.68) for scores of 0-4, compared to Apgar scores of 9-10. Elective Caesarean sections were associated with an increased risk of ADHD with an adjusted odds ratio of 1.15 (95% CI 1.05-1.26). Other identified risk factors were breech presentation, induced labour and admission to a neonatal intensive care unit. Low umbilical artery pH did not increase the risk of ADHD. CONCLUSION: Elective Caesareans and perinatal adversities leading to lower Apgar scores increased the risk of ADHD. Future research to identify the mechanisms behind these findings is warranted.

Dr. Sucksdorff et al. Reply.

We thank Trivedi et al. for their letter1 raising valuable questions regarding a clinical viewpoint on the observed association between maternal vitamin D levels in early pregnancy and offspring risk of attention-deficit/hyperactivity disorder (ADHD) in our study.2 We are happy that our research has raised discussion and are grateful for the opportunity to reply.

Maternal Vitamin D Levels and the Risk of Offspring Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Recent evidence has highlighted the importance of vitamin D in the development of the central nervous system. Some studies have shown an association between maternal vitamin D deficiency during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD) symptoms based on parent or teacher ratings. There are no previous studies on early pregnancy 25-hydroxyvitamin D [25(OH)D] levels and the risk of diagnosed offspring ADHD. Our aim was to examine maternal 25(OH)D levels in early pregnancy and offspring ADHD. METHOD: In this nationwide population-based case-control study, 1,067 ADHD cases (born between 1998 and 1999 and diagnosed according to the International Classification of Diseases) and 1,067 matched controls were identified from Finnish registers. Maternal 25(OH)D levels were measured using quantitative immunoassay from maternal sera, collected during the first trimester and archived in the national biobank. Conditional logistic regression was used to examine the association between maternal 25(OH)D and offspring ADHD. RESULTS: There was a significant association between decreasing log-transformed maternal 25(OH)D levels and offspring ADHD both in the unadjusted analyses (odds ratio 1.65; 95% CI 1.33-2.05; p < .001) and in the analyses adjusting for maternal socioeconomic status and age (odds ratio 1.45; 95% CI 1.15-1.81; p = .002). Analyses by quintiles of maternal 25(OH)D levels in the lowest versus highest quintile revealed an adjusted odds ratio for offspring ADHD of 1.53 (95% CI 1.11-2.12; p = .010). CONCLUSION: This study demonstrated an association between low maternal 25(OH)D during pregnancy and an elevated risk for offspring ADHD. If replicated in independent samples, this finding may have significant public health implications.

Maternal Vitamin D Levels During Pregnancy and Offspring Autism Spectrum Disorder.

BACKGROUND: Findings from previous studies on maternal 25-hydroxyvitamin D [25(OH)D] levels during pregnancy and autism spectrum disorder (ASD) in offspring are inconsistent. METHODS: The association between maternal 25(OH)D levels during pregnancy and offspring ASD was examined using data from a nationwide population-based register with a nested case-control study design. The ASD cases (n = 1558) were born between 1987 and 2004 and received a diagnosis of ASD by 2015; cases were matched with an equal number of controls. Maternal 25(OH)D levels during pregnancy were measured using quantitative immunoassay from maternal sera collected during the first and early second trimesters and archived in the national biobank of the Finnish Maternity Cohort. Conditional logistic regression examined the association between maternal 25(OH)D levels and offspring ASD. RESULTS: In the adjusted model, there was a significant association between increasing log-transformed maternal 25(OH)D levels and decreasing risk of offspring ASD (adjusted odds ratio [aOR] 0.75, 95% confidence interval [CI] 0.62-0.92, p = .005). Analyses by quintiles of maternal 25(OH)D levels revealed increased odds for ASD in the 2 lowest quintiles, <20 (aOR 1.36, 95% CI 1.03-1.79, p = .02) and 20-39 (aOR 1.31, 95% CI 1.01-1.70, p = .04), compared with the highest quintile. The increased risk of ASD was observed in association with deficient (<30 nmol/L) (aOR 1.44, 95% CI 1.15-1.81, p = .001) and insufficient (30-49.9 nmol/L) maternal 25(OH)D levels (aOR 1.26, 95% CI 1.04-1.52, p = .01) compared with sufficient levels. CONCLUSIONS: This finding has implications for understanding the role of maternal vitamin D during fetal brain development and increased risk of ASD.

Preterm Birth Is Associated With Depression From Childhood to Early Adulthood.

OBJECTIVE: There have been inconsistent findings on the associations among prematurity, poor fetal growth, and depression. We examined the associations among gestational age, poor fetal growth, and depression in individuals aged 5 to 25 years. METHOD: We identified 37,682 case subjects based on International Classification of Diseases, Ninth Revision code 2961 and International Classification of Diseases, Tenth Revision codes F32.0-F32.9 and F33.0-F33.9 from the Care Register for Health Care, and 148,795 matched controls from the Finnish Central Population Register. Conditional logistic regression examined the associations between gestational age by each gestational week, poor fetal growth, and depression. The associations were adjusted for parental age and psychopathology, paternal immigrant status, maternal substance abuse, depression, number of previous births, marital status, socio-economic status, smoking during pregnancy, and the infant's birthplace. RESULTS: In the adjusted models, increased risk of depression was found in children born ≤25 weeks (adjusted odds ratio [aOR] 1.89, 95% CI 1.08-3.31), at 26 weeks (aOR 2.62, 95% CI 1.49-4.61), at 27 weeks (aOR 1.93, 95% CI 1.05-3.53), and ≥42 weeks (aOR 1.11, 95% CI 1.05-1.19). In girls, extremely preterm birth was associated with depression diagnosed at 5 to 12 years (aOR 2.70, 95% CI 1.83-3.98) and 13 to 18 years (aOR 2.97, 95% CI 1.84-4.78). In boys, postterm birth (≥42 weeks) was associated with depression diagnosed at 19 to 25 years (aOR 1.28, 95% CI 1.07-1.54). Poor fetal growth was associated with an increased risk of depression in full-term infants (aOR 1.06, 95% CI 1.03-1.10) and postterm infants (aOR 1.24, 95% CI 1.08-1.43). CONCLUSION: Preterm birth before 28 weeks of gestation appeared to play a role in the development of childhood depression. Smaller effects were also seen in postterm births, especially in boys.

Prenatal Cotinine Levels and ADHD Among Offspring.

OBJECTIVES: An association between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder (ADHD) has been shown across several studies based on self-reports. No previous studies have investigated the association of nicotine exposure measured by cotinine levels during pregnancy and offspring ADHD. METHODS: In this population-based study, 1079 patients born between 1998 and 1999 and diagnosed with ADHD according to the International Classification of Diseases and 1079 matched controls were identified from Finnish nationwide registers. Maternal cotinine levels were measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank. RESULTS: There was a significant association between increasing log-transformed maternal cotinine levels and offspring ADHD. The odds ratio was 1.09 (95% confidence interval [CI] 1.06-1.12) when adjusting for maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child's birth weight for gestational age. In the categorical analyses with cotinine levels in 3 groups, heavy nicotine exposure (cotinine level >50 ng/mL) was associated with offspring ADHD, with an odds ratio of 2.21 (95% CI 1.63-2.99) in the adjusted analyses. Analyses by deciles of cotinine levels revealed that the adjusted odds for offspring ADHD in the highest decile was 3.34 (95% CI 2.02-5.52). CONCLUSIONS: The study reveals an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD. Future studies incorporating maternal smoking and environmental, genetic, and epigenetic factors are warranted.

Preterm Birth and Poor Fetal Growth as Risk Factors of Attention-Deficit/ Hyperactivity Disorder.

BACKGROUND: Previous studies have shown an association between prematurity and attention- abstract deficit/hyperactivity disorder (ADHD). Results concerning late preterm infants are controversial, and studies examining fetal growth represented by weight for gestational age are scarce. Our objective was to examine the association between gestational age by each week of fetal maturity, weight for gestational age, and ADHD. METHODS: In this population-based study, 10 321 patients with ADHD, diagnosed according to the International Classification of Diseases and 38 355 controls individually matched for gender, date and place of birth, were identified from Finnish nationwide registers. Perinatal data were obtained from the Finnish Medical Birth Register. Conditional logistic regression was used to examine the association between gestational age, weight for gestational age, and ADHD after controlling for confounding factors. RESULTS: The risk of ADHD increased by each declining week of gestation. The associations were robust after adjusting for confounders. An elevated risk also was seen among late preterm and early term infants. As for fetal growth, the odds ratio showed a U-shaped curve with an increased risk seen when the weight for gestational age was 1 SD below and 2 SD above the mean. CONCLUSIONS: Our findings suggest that each gestational week has significance for child's subsequent neurodevelopment and risk for ADHD. We also showed that poor fetal growth increased the risk of ADHD. This highlights the importance of taking into account both prematurity and poor fetal growth when planning the timing of birth as well as later follow-up and support policies.