Infertility Treatment and Autism Risk Using the Modified Checklist for Autism in Toddlers (M-CHAT)

S.L. Robinson; T. Parikh; T. Lin; E.M. Bell; E. Heisler; H. Park; C. Kus; J.E. Stern; E.H. Yeung


Hum Reprod. 2020;35(3):684-693. 

In This Article

Abstract and Introduction


Study Question: Are toddlers conceived by fertility treatment at higher risk of failing a screening tool for autism spectrum disorders (ASD) than toddlers not conceived by treatment?

Summary Answer: Compared with children not conceived by infertility treatment, children conceived by any infertility treatment, ovulation induction with or without intrauterine insemination (OI/IUI), or assisted reproductive technologies (ART) appeared to have had higher odds of failing an ASD screening; however, results were inconclusive and need replication.

What is Known Already: Although most of the studies which have examined risk of ASD after ART show no association, the results are mixed. Thus, further studies are needed to clarify this association.

Study Design Size, Duration: The Upstate KIDS Study is a population-based, prospective cohort study of children born in New York State between 2008 and 2010. Children were screened for ASD using the Modified Checklist for Autism in Toddlers (M-CHAT) at ages 18 and 24 months.

Participants/Materials, Setting, and Methods: The New York State live-birth registry was used to identify newborns conceived with and without fertility treatment with a 1:3 ratio, frequency matched on region of birth. At 18 and 24 months, 3183 and 3063 mothers, respectively, completed the M-CHAT questionnaire. The current analysis included 2586 singletons and 1296 twins with M-CHAT information at 18 and/or 24 months. Multivariable logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (aOR) and 95% confidence intervals (CI) after adjustment for covariates such as maternal age, education and plurality.

Main Results and the Role of Chance: We found that 200 (5.2%) and 115 (3.0%) children failed the M-CHAT at 18 and 24 months, respectively. The associations between use of infertility treatment and failing the M-CHAT at 18 and/or 24 months were positive but inconclusive as they failed to exclude no association (18 months aOR 1.71, 95% CI: 0.81–3.61; 24 months aOR 1.78, 95% CI: 0.66–4.81; and both 18 and 24 months aOR 1.53, 95% CI: 0.78–2.99). The relationships between OI/IUI and ART with M-CHAT failure at 18 and/or 24 months were similar to those of using any fertility treatment. In vitro fertilization with intracytoplasmic sperm injection was not consistently positively or inversely associated with M-CHAT failure at each time point (18 months aOR 1.20, 95% CI: 0.51–2.83; 24 months aOR 0.93, 95% CI: 0.37–2.31; and both 18 and 24 months aOR 1.09, 95% CI: 0.50–2.60).

Limitations Reasons for Caution: The M-CHAT is a screening tool used for ASD risk assessment, and therefore, M-CHAT failure does not indicate ASD diagnosis. In addition, we did not have power to detect associations of small magnitude. Finally, non-response to follow-up may bias the results.

Wider Implications of the Findings: Despite lack of precision, the positive associations between ART and M-CHAT failure suggest that larger population-based studies with longer follow-up are needed.

Study Funding/Competing Interest(S): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, HHSN267200700019C). The sponsor played no role in the study design, data collection, data analysis or interpretation, writing of the manuscript or decision to submit the article for publication. There are no conflicts of interest to declare.

Trial Registration Number: Not applicable.


The increasing use of fertility treatments, specifically ART, has helped many couples become parents. As ART gains popularity, concerns remain regarding the potential health and developmental consequences of controlled ovarian hyperstimulation, IVF and ICSI often used to assist in achieving conception (Agarwal et al., 2005; Catford et al., 2017; Conti et al., 2013). It has been reported, for example, that ART use is associated with increased risk of congenital malformations and nervous systems defects (Qin et al., 2015).

Of particular interest is the potential relation between ART use and autism spectrum disorder (ASD). ASD is a neurodevelopmental condition often diagnosed within the first few years of childhood characterized by impaired social interaction or communication, together with restricted and repetitive behaviors (American Psychiatric Association, 2013). According to the Centers for Disease Control and Prevention, 1 in 59 children have ASD, with an observed increase in the prevalence of ASD diagnoses over the past two decades (Baio et al., 2018; Christensen et al., 2016). An increase in diagnosis only partially accounts for the rise in ASD, which highlights the importance of understanding what factors may contribute to this trend (Polyak et al., 2015).

Although the exact causes of ASD are unknown, both environmental and genetic factors have been associated with ASD. Specific to ART, exposures associated with increased infertility such as older paternal age, sperm quality and maternal infertility diagnoses have been related to risk of ASD in the offspring (Grether et al., 2013; Jenkins et al., 2014; Schieve et al., 2017; Sharma et al., 2015). General use of ART has been associated with ASD diagnosis in a large retrospective cohort study in California, in a case-control study in India and among a subgroup of children with mothers older than 35 years in the USA (Lyall et al., 2012; Mamidala et al., 2013; Fountain et al., 2015). However, results from additional studies are mixed, with several studies finding null associations (Hvidtjorn et al., 2011; Lehti et al., 2013; Lyall et al., 2013; Diop et al., 2019) and one (Maimburg and Vaeth, 2007) finding an inverse association. Further, there is evidence of a stronger association in twins (Grether et al., 2013; Fountain et al., 2015) compared to singletons. Additionally, researchers have studied the associations of specific infertility interventions and procedures with ASD, as summarized in two recent systematic reviews (Conti et al., 2013; Catford et al., 2017). In short, two studies found ICSI use during IVF treatment to be associated with increased risk of ASD compared with IVF treatment without ICSI (Sandin et al., 2013; Kissin et al., 2015). Hormonal interventions involved in ovulation induction with or without intrauterine insemination (OI/IUI) have been related to ASD in some studies (Lyall et al., 2012; Grether et al., 2013; Davidovitch et al., 2018) but not in others (Hvidtjorn et al., 2011; Lyall et al., 2013; Mamidala et al., 2013; Schieve et al., 2017). Given the wide use of ART nationally and conflicting results from previous studies, it is important to further examine these associations.

Early detection and intervention in ASD can improve developmental and behavioral outcomes (Daniel et al., 2009). Although age at ASD diagnosis has decreased since the mid-1990s in the USA (Parner et al., 2008), most children are still diagnosed later in childhood, with median age of diagnosis being 50 months (Christensen et al., 2018). Early ASD diagnosis is more common among children of women with higher socioeconomic status (Jo et al., 2015), which may reflect the ability of these women to better recognize early symptoms and navigate the health care system rather than population-level differences in ASD prevalence. Indeed, there is evidence that the ART and ASD association could be influenced by systematic differences in ASD diagnosis by socioeconomic status (Schieve et al., 2015). For these reasons, accessible screening assessment tools that aid in early detection and follow-up of children presenting with developmental findings concerning for ASD are essential and studies using these instruments may help address diagnostic biases which could have influenced previous investigations. Currently, several such autism-specific screening tools exist. For young children, the most prominently used is the Modified Checklist for Autism in Toddlers (M-CHAT), which utilizes a parent-based questionnaire to yield risk of autism development in a child at ages 18 and 24 months.

Given the prior evidence that children conceived with infertility treatment may be at high risk for the development of ASD, we sought to examine whether conception with infertility treatment was related to increased risk of failing the M-CHAT, an early ASD screening tool, within the Upstate KIDS Study, a prospective cohort study which oversampled children of mothers who used infertility treatments. Additionally, we assessed whether the association with ASD screening results varied by mode of infertility treatment, such as OI/IUI or ART with or without ICSI. We hypothesize that the use of ART and other fertility treatments may be associated with increased M-CHAT failures.