Hui Wang1, Fei Li1, Maohua Miao2, Yongfu Yu3, Honglei Ji2, Hui Liu4, Rong Huang1, Carsten Obel5, Jun Zhang1, Jiong Li1,3. 1. MOE-Shanghai Key Laboratory of Children's Environmental Health, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. NHC Key Lab. of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China. 3. Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark. 4. School of Public Health/Medical Informatics Center, Peking University, Beijing, China. 5. Unit of Mental Public Health, Department of Public Health, Aarhus University, Aarhus, Denmark.
Abstract
STUDY QUESTION: Is a maternal history of spontaneous abortion (SA) associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring? SUMMARY ANSWER: Our results suggest an association between maternal history of SA and ADHD in offspring, with the risk increasing with the number of maternal SA and highest in the firstborn children whose mothers had had recurrent SAs after adjusting for a number of potential confounders. WHAT IS KNOWN ALREADY: A history of SA has been associated with more complications in next pregnancies and adverse childbirth outcomes, which are risk factors for ADHD in the offspring. However, no previous study has investigated whether maternal SA increases risk of ADHD in the offspring. STUDY DESIGN, SIZE, DURATION: This population-based study included all live-born children in Denmark from 1 January 1995 to 31 December 2012 (n = 1 062 667). All children were followed from 3 years of age until the day of ADHD diagnosis, death, emigration or 31 December 2016, whichever came first. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 130 206 (12.2%) children born to mothers who had at least one SA. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). MAIN RESULTS AND THE ROLE OF CHANCE: During a median follow-up of 9.4 years (interquartile range, 5.4-14.3), 25 747 children were diagnosed with ADHD. Overall, children of mothers with a history of SA had an increased rate of ADHD (HR, 1.11; 95% CI, 1.07 to 1.15). The HRs increased with the number of maternal SA, 1.09 (95% CI, 1.05 to 1.13) for one SA and 1.22 (95% CI, 1.12 to 1.33) for at least two SAs, respectively. These findings were consistent when we took into consideration a number of factors, such as maternal socioeconomic status, type of SA, birth order, parental history of psychiatric disorders, pregnancy characteristics and adverse birth outcomes. LIMITATIONS, REASONS FOR CAUTION: Misclassification of SA was possible as we used population-based register data to capture maternal history of SA. However, any misclassification of maternal history of SA would be non-differential with regard to the diagnosis of ADHD in offspring, which generally leads to underestimation of the associations. Furthermore, probabilistic sensitivity analysis suggested that only 1% of change in the estimate may have been due to misclassification of SA. WIDER IMPLICATIONS OF THE FINDINGS: SA is quite frequent (varying from 15 to 20%), and a small increase of neurodevelopmental problems in offspring could have major public health implications. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Natural Science Foundation of China (No. 81703237, No. 81530086 and No. 81761128035), National Key Research and Development Program (2018YFC1002801, 2016YFC1000505), Shanghai Municipal Commission of Health and Family Planning (No. 2017ZZ02026, No. 2017EKHWYX-02), the Novo Nordisk Foundation (NNF18OC0052029), the Danish Council for Independent Research (DFF-6110-00019), the Nordic Cancer Union (176673, 186200 and R217-A13234-18-S65), Karen Elise Jensens Fond (2016) and Xinhua Hospital of Shanghai Jiao Tong University School of Medicine (2018YJRC03). All authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NA.
STUDY QUESTION: Is a maternal history of spontaneous abortion (SA) associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring? SUMMARY ANSWER: Our results suggest an association between maternal history of SA and ADHD in offspring, with the risk increasing with the number of maternal SA and highest in the firstborn children whose mothers had had recurrent SAs after adjusting for a number of potential confounders. WHAT IS KNOWN ALREADY: A history of SA has been associated with more complications in next pregnancies and adverse childbirth outcomes, which are risk factors for ADHD in the offspring. However, no previous study has investigated whether maternal SA increases risk of ADHD in the offspring. STUDY DESIGN, SIZE, DURATION: This population-based study included all live-born children in Denmark from 1 January 1995 to 31 December 2012 (n = 1 062 667). All children were followed from 3 years of age until the day of ADHD diagnosis, death, emigration or 31 December 2016, whichever came first. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 130 206 (12.2%) children born to mothers who had at least one SA. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). MAIN RESULTS AND THE ROLE OF CHANCE: During a median follow-up of 9.4 years (interquartile range, 5.4-14.3), 25 747 children were diagnosed with ADHD. Overall, children of mothers with a history of SA had an increased rate of ADHD (HR, 1.11; 95% CI, 1.07 to 1.15). The HRs increased with the number of maternal SA, 1.09 (95% CI, 1.05 to 1.13) for one SA and 1.22 (95% CI, 1.12 to 1.33) for at least two SAs, respectively. These findings were consistent when we took into consideration a number of factors, such as maternal socioeconomic status, type of SA, birth order, parental history of psychiatric disorders, pregnancy characteristics and adverse birth outcomes. LIMITATIONS, REASONS FOR CAUTION: Misclassification of SA was possible as we used population-based register data to capture maternal history of SA. However, any misclassification of maternal history of SA would be non-differential with regard to the diagnosis of ADHD in offspring, which generally leads to underestimation of the associations. Furthermore, probabilistic sensitivity analysis suggested that only 1% of change in the estimate may have been due to misclassification of SA. WIDER IMPLICATIONS OF THE FINDINGS: SA is quite frequent (varying from 15 to 20%), and a small increase of neurodevelopmental problems in offspring could have major public health implications. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Natural Science Foundation of China (No. 81703237, No. 81530086 and No. 81761128035), National Key Research and Development Program (2018YFC1002801, 2016YFC1000505), Shanghai Municipal Commission of Health and Family Planning (No. 2017ZZ02026, No. 2017EKHWYX-02), the Novo Nordisk Foundation (NNF18OC0052029), the Danish Council for Independent Research (DFF-6110-00019), the Nordic Cancer Union (176673, 186200 and R217-A13234-18-S65), Karen Elise Jensens Fond (2016) and Xinhua Hospital of Shanghai Jiao Tong University School of Medicine (2018YJRC03). All authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NA.
Authors: Stephen V Faraone; Tobias Banaschewski; David Coghill; Yi Zheng; Joseph Biederman; Mark A Bellgrove; Jeffrey H Newcorn; Martin Gignac; Nouf M Al Saud; Iris Manor; Luis Augusto Rohde; Li Yang; Samuele Cortese; Doron Almagor; Mark A Stein; Turki H Albatti; Haya F Aljoudi; Mohammed M J Alqahtani; Philip Asherson; Lukoye Atwoli; Sven Bölte; Jan K Buitelaar; Cleo L Crunelle; David Daley; Søren Dalsgaard; Manfred Döpfner; Stacey Espinet; Michael Fitzgerald; Barbara Franke; Manfred Gerlach; Jan Haavik; Catharina A Hartman; Cynthia M Hartung; Stephen P Hinshaw; Pieter J Hoekstra; Chris Hollis; Scott H Kollins; J J Sandra Kooij; Jonna Kuntsi; Henrik Larsson; Tingyu Li; Jing Liu; Eugene Merzon; Gregory Mattingly; Paulo Mattos; Suzanne McCarthy; Amori Yee Mikami; Brooke S G Molina; Joel T Nigg; Diane Purper-Ouakil; Olayinka O Omigbodun; Guilherme V Polanczyk; Yehuda Pollak; Alison S Poulton; Ravi Philip Rajkumar; Andrew Reding; Andreas Reif; Katya Rubia; Julia Rucklidge; Marcel Romanos; J Antoni Ramos-Quiroga; Arnt Schellekens; Anouk Scheres; Renata Schoeman; Julie B Schweitzer; Henal Shah; Mary V Solanto; Edmund Sonuga-Barke; César Soutullo; Hans-Christoph Steinhausen; James M Swanson; Anita Thapar; Gail Tripp; Geurt van de Glind; Wim van den Brink; Saskia Van der Oord; Andre Venter; Benedetto Vitiello; Susanne Walitza; Yufeng Wang Journal: Neurosci Biobehav Rev Date: 2021-02-04 Impact factor: 9.052