Maternal Spontaneous Abortion and the Risk of Attention-deficit/Hyperactivity Disorder in Offspring

A Population-based Cohort Study

Hui Wang; Fei Li; Maohua Miao; Yongfu Yu; Honglei Ji; Hui Liu; Rong Huang; Carsten Obel; Jun Zhang; Jiong Li


Hum Reprod. 2020;35(5):1211-1221. 

In This Article

Abstract and Introduction


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.


Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders (Visser et al., 2014). ADHD often emerges during childhood and persists into adulthood (Mannuzza et al., 2003), with prevalence ranging from 3 to 7% globally (Sayal et al., 2018) and even up to 10% reported in recent studies (Visser et al., 2014; Thomas et al., 2015). Given the fact that ADHD can have negative impacts on patients and their families and even society at large, identification of ADHD risk factors has major public health significance (Galéra et al., 2011; Shaw et al., 2012).

The aetiology of ADHD is complex and remains mostly unknown (Faraone et al., 2005; Millichap, 2008). An increasing body of evidence has suggested a role of foetal programming on ADHD development (Sciberras et al., 2017). Prenatal exposure to adverse intrauterine environment could lead to an increased susceptibility to neurodevelopmental disorders later in life (Bale et al., 2010). Maternal fertility problems may be linked to factors that also influence offspring's neurodevelopment and ADHD risk (Bay et al., 2013; Svahn et al., 2015). Spontaneous abortion (SA) is one of the common adverse pregnancy outcomes, affecting ~20% of pregnant women with recurrent rates of 1 to 2% (Sedgh et al., 2016). Women with a history of SA are more likely to have pregnancy complications, such as gestational diabetes (Bhattacharya et al., 2008), impaired placentation (Gunnarsdottir et al., 2014) and heightened oxidative stress (Jauniaux et al., 2006), which may predispose children to developing ADHD (Getahun et al., 2013). Women with SA often give birth to children with more adverse birth outcomes, such as preterm birth, low birth weight, congenital anomalies and lower Apgar score (Brown et al., 2008), which have been demonstrated to be risk factors for ADHD (Li et al., 2011; Sucksdorff et al., 2015). For example, a population-based study in Norway reported a 1.3- and 5-fold risk for ADHD in individuals born preterm (<37 gestational weeks) and extremely preterm (<28 gestational weeks), respectively (Rommel et al., 2017). Furthermore, the risk of those adverse birth outcomes is increased with the number of previous SA (Brown et al., 2008; Ahrens et al., 2016). One study has further shown an association between maternal history of SA and epilepsy (Schupf and Ottman, 2001). However, it is not known whether maternal history of SA increases the risk of ADHD in the offspring. Previous studies have also shown a bidirectional association between SA and psychiatric disorders in women (Fergusson et al., 2008; Toffol et al., 2013), suggesting a role of shared genetic susceptibility and family environment (Fergusson et al., 2008; Toffol et al., 2013).

We hypothesized that maternal SA may lead to an increased risk of ADHD in offspring and the magnitude of risk might differ by the number of maternal SA. Previous studies have suggested that birth order may also signify different levels of hormone exposure in utero (Bernstein et al., 1986; Von Behren et al., 2011) that may affect the risk of ADHD in the offspring (Carballo et al., 2013). In this large nationwide cohort study of >1 million persons with a long follow-up in Denmark, we aimed to investigate the association between maternal history of SA and ADHD in offspring, taking into consideration a number of maternal and offspring characteristics, such as sociodemographic factors, pregnancy complications, birth order and adverse birth outcomes (Bhattacharya et al., 2008; Brown et al., 2008; Li et al., 2011; Von Behren et al., 2011; Toffol et al., 2013; Sucksdorff et al., 2015; Rommel et al., 2017).