Assisted reproductive technology and risk for autism spectrum disorder
Highlights
► Increased rate of assisted reproductive technology is documented in a large group with well-defined autism spectrum disorder. ► Although maternal age is more advanced in the ASD group, even young mothers (<29 years) have increased rates of ART. ► Confounding risk factors for ASD, prematurity, low birth weight and genetic susceptibility do not affect ART rate in ASD. ► Assisted conception is not related to a unique clinical profile in ASD.
Introduction
Autism spectrum disorders (ASD) are a group of neurobehavioral disorders defined by social and communication deficits and repetitive and stereotyped behaviors. ASD comprise a spectrum delineated by a set of observable dysfunctions and has wide variability with respect to the presence and intensity of the core symptoms and cognitive and language skills (Johnson & Myers, 2007). The current estimated prevalence of ASD is approximately 1:100–150 (Kogan et al., 2009), which reflects a 15-fold increase from studies published a half-century ago. ASD are biologically based disorders that are highly heritable. The exact cause of ASD is still unknown and therefore it is now believed that despite the strong genetic origin, environmental factors may modulate phenotypical expression (Johnson and Myers, 2007, Kogan et al., 2009).
Several environmental risk factors have been suggested as playing a role in ASD. Symptoms of autism can be identified as early as in the first 2 years of life. Therefore, pre-and perinatal events are now the focus of research into risk factors for ASD. Birth risk factors during the first and second trimesters of pregnancy play a role in the fetus via maternal factors and may cause many of the developmental brain abnormalities known to be associated with ASD (Larsson et al., 2005). Several studies from Sweden (Juul-Dam, Townsend, & Courchesne,2001), Denmark (Larsson et al., 2005), Australia (Williams, Helmer, Duncan, Peat, & Mellis, 2008), and the US (Brimacombe, Ming, & Lamendola, 2007) reported birth risk factors that are related to ASD. Maternal and pregnancy risk factors that were significantly associated with autism are obstetric complications, such as hypoxia-related conditions (bleeding in pregnancy, Brimacombe et al., 2007, Hultman et al., 2002; prolonged labor, Brimacombe et al., 2007; caesarian delivery, Hultman et al., 2002; low Apgar scores, Larsson et al., 2005), advanced maternal and paternal age (>35 years), Hultman et al., 2002, Williams et al., 2008; perinatal factors, such as gestational age, (Brimacombe et al., 2007, Larsson et al., 2005, Williams et al., 2008), male gender and low birth weight (LBW) (Gardener et al., 2009, Grether et al., 2009, Kolevzon et al., 2007). None of these factors was consistently associated with ASD (Gardener et al., 2009).
Since 1973, more than a million children have been conceived through assisted reproductive technology (ART). Although the techniques are considered safe, in recent years there is accumulating evidence that ART may be associated with an increased risk of birth defects, LBW, and genetic imprinting disorders (Gosden et al., 2003, Hansen et al., 2002, Merlob et al., 2005). The prevalence of major malformations in different studies has ranged from 5.6 to 9.0% in comparison to 4.2–5% in the general population (Hansen et al., 2002, Merlob et al., 2005). Children arising from ART were also at higher risk for epigenetic and imprinted disorders (Cox et al., 2002, Lidegaard et al., 2006). The use of assisted reproductive techniques, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), has increased over the last two decades. Therefore, association between this increase in ART procedures and the increase in ASD prevalence has been suggested. Previous research has attempted to assess the risk for ASD in children born after assisted conception and found conflicting results (reviewed in Hvidtjørn et al., 2009). Several retrospective studies (Ericson et al., 2002, Klemetti et al., 2006, Knoester et al., 2007, Pinborg et al., 2003) and one case-control study (Stein, Weizman, Ring, & Barak, 2006) reported an increased risk for autism/ASD, while others did not find higher occurrence of ASD (Hvidtjørn et al., 2010, Lidegaard et al., 2005, Maimburg and Vaeth, 2007, Strömberg et al., 2002) in children born after ART. All but two of the studies [one Israeli (Stein et al., 2006) and one from the Netherlands (Knoester et al., 2007)] originated in Scandinavian countries. In addition, diagnosis of ASD was based in most studies on ICD-10 classification (World Health Organization, 1992) except for one study on ASD population from Israel that was based on DSM-III, IV criteria (American Psychiatric Association, 1994).
This study was designed as a case–control study that focused on the association between ART and ASD in a large Israeli population diagnosed with ASD using stringent criteria based on standardized tests. The study had three main aims. The first aim was to assess the frequencies of ART in a group with ASD and compare them to a large Israeli population. The populations of ASD and ART share several risk factors including advanced parental ages, prematurity and low birth weight. Therefore, the second aim of this study focused on possible confounding birth and familial risk factors in the ASD group that underwent an ART procedure. Different etiologies for ASD can contribute to the variability in clinical expressions in ASD. Therefore, the third aim was to look for a unique clinical profile in individuals with ASD that underwent assisted conception by comparing them to individuals with ASD without a history of ART in autism severity, adaptive skills and developmental regression.
Section snippets
Setting and procedures
The study was conducted at the Autism Center, a national tertiary center housed within Assaf Harofeh Medical Center in Israel, whose services include diagnosis treatment and research. The children were referred to the Autism Center for a comprehensive assessment of possible diagnosis of ASD by pediatricians, teachers, paramedical professionals and parents. The evaluation included a neurological assessment by a pediatric developmental neurologist, and behavioral and adaptive functioning
Rate of ART
Of the participants diagnosed with ASD, 54 (10.7%) were conceived by ART. This rate of ART pregnancies was significantly higher than the number of ART pregnancies in the Israeli newborn cohort of 3.06% (Merlob et al., 2005) (χ2 = 93.2, p < .001). The frequency of ART in a subgroup of the ASD group born during the same time period as the Israeli population (1995–2002) (N = 285) was 8.1% (N = 23) and was not statistically different from the frequency of ART in the entire ASD group (χ2 = 1.2, p > .05), but
Discussion
This is a pilot study that investigated the potential association between assisted conception and risk of autism spectrum disorders. We found a significantly higher prevalence of assisted reproductive technologies (IVF and ICSI) (10.7%) among a large clinic-based well characterized ASD population in comparison to the rate of ART (3.06%) in a large Israeli population. The ART rate in Israel is considered high in comparison to the United States (1.0%) (U.S. Department of Health and Human
Conclusion
Our study showed that the rate of assisted conception was high in a large ASD group. ART appears to be a significant independent risk factor for ASD unassociated with other established risk factors for ASD, including advanced maternal age, prematurity, low birth weight and history of ASD in the family. Although assisted conception might be a risk factor for autism, this group did not appear to represent a separate clinical phenotype within the autism spectrum.
In light of this study results, a
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2015, Handbook of Fertility: Nutrition, Diet, Lifestyle and Reproductive HealthParent-reported use of assisted reproduction technology, infertility, and incidence of autism spectrum disorders
2015, Research in Autism Spectrum DisordersCitation Excerpt :The incidence of birth defects in children conceived via certain types of ART (ART+) is higher than that noted in the rest of the population (e.g., CDC, 2009; Davies et al., 2012). Compared to children conceived without the use of ART (ART−), the CDC (2011) reports a higher risk of pre-term delivery and of low and very low birth weight (c.f. Zachor & Itzchak, 2011) and an increased probability of multiple-fetus pregnancy associated with various types of ART use (Lu et al., 2013). Even singleton infants conceived via ART are reported to be at a higher risk for adverse perinatal outcomes, compared to infants conceived without the use of ART (Davies et al., 2012; Knoester et al., 2008).
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2022, Autism Spectrum Disorder: Symptoms, Diagnosis and Types of TreatmentIntracytoplasmic sperm injection and fetal origins of autism spectrum disorder: an intriguing, though controversial association
2022, Journal of Maternal-Fetal and Neonatal Medicine
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