摘要：Objectives. We assessed the association between assisted reproductive technology (ART) and diagnosed autistic disorder in a population-based sample of California births. Methods. We performed an observational cohort study using linked records from the California Birth Master Files for 1997 through 2007, the California Department of Developmental Services autism caseload for 1997 through 2011, and the Centers for Disease Control and Prevention’s National ART Surveillance System for live births in 1997 through 2007. Participants were all 5 926 251 live births, including 48 865 ART-originated infants and 32 922 cases of autism diagnosed by the Department of Developmental Services. We compared births originated using ART with births originated without ART for incidence of autism. Results. In the full population, the incidence of diagnosed autism was twice as high for ART as non-ART births. The association was diminished by excluding mothers unlikely to use ART; adjustment for demographic and adverse prenatal and perinatal outcomes reduced the association substantially, although statistical significance persisted for mothers aged 20 to 34 years. Conclusions. The association between ART and autism is primarily explained by adverse prenatal and perinatal outcomes and multiple births. Autism spectrum disorder (ASD) is a serious developmental disability characterized by deficits of communication and social interaction and often accompanied by restricted or repetitive behaviors. Recent surveillance efforts estimate ASD to occur in 1 in 68 US children aged 8 years, with rapid increases in identified incidence over the past decade. 1 Numerous studies have investigated the causes and correlates of autism and ASD, commonly finding male gender 2,3 ; prenatal and perinatal factors, 4–6 such as preterm birth, low birth weight, and gestational diabetes; and parental characteristics, such as higher socioeconomic status 5 and education, 2,5 older parental age, 2,3,7,8 White race, 2,5 and history of psychiatric conditions 4 to be associated with autism. In addition, there is a large but complex genetic component with a subset of inherited familial autism cases as well as an important role for rare and common copy number variations. 9–11 As autism diagnoses have risen, the use of assisted reproductive technology (ART), defined as in vitro fertilization (IVF) and similar procedures in which both egg and sperm are handled, has increased rapidly. 12 In a typical ART procedure, fresh or frozen egg and sperm from donors or from 1 or both of the parents are combined in a laboratory for fertilization and cultured for several days before implantation in a woman’s uterus. 13 Often hormonal medication is used to stimulate or regulate ovulation. There are several variations, including IVF with intracytoplasmic sperm injection, in which the egg is fertilized by injecting the sperm directly into the egg, and less common procedures, in which the fertilized embryo, or a mixture of sperm and eggs, is placed in the fallopian tubes rather than the uterus (zygote intrafallopian transfer and gamete intrafallopian transfer, respectively). Often, multiple embryos are transferred to maximize the probability of implantation and pregnancy, producing a high rate of twin and higher-order multiple births from ART. In recent years, the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine have issued voluntary guidelines regarding the number of embryos to transfer for various patient types, which has resulted in a reduction in multiple births. 14 ART-originated pregnancies share many of the correlates of autism, including parents who are older and have higher levels of education and multiple births, preterm delivery, pregnancy and labor complications, low birth weight, and other birth defects and developmental disabilities. Further, the use of ART contributes to the preexisting trend of older parents by pushing on the upper boundary of the fertile age range. A few studies have investigated the relationship between ART conception and the risk of developmental disabilities and autism diagnoses; however, results are mixed and inconclusive. 15–25 For example, some studies have found no differences between children originated with ART and control groups of children with regard to congenital malformation or developmental delay, 26 but others have found increased risks of emotional disturbances, 27 lower cognitive and language skills, 28 and cerebral palsy. 20 In a recent review of the evidence on the ART–autism association 8 studies, many with design limitations including short follow-up periods and insufficient sample sizes, showed inconsistent results. 20 Most studies that have examined ART outcomes have failed to collect data from participants older than 2 years 29 ; this is a problem because autism is often diagnosed when a child is older than 4 years. 1 One recent case-control study found no association, although there was some evidence of a link between less severe forms of ASD and artificial insemination and ovulation-induction treatment among older mothers. 23 A study of children with ASD found no evidence of increased copy number variations or other autism-related genetic events among children originated with ART. 30 The best evidence comes from several well-designed Scandinavian studies using large population-level registry databases. A Danish study found an elevated risk of autism for infants originated through ART, although the difference was not statistically significant after adjustments. 18 However, this study did find elevated risks for certain subgroups, notably girls and those born after ovarian stimulation treatment. Another Danish registry study found no increased risk of childhood and adolescent psychological disorders resulting from IVF, but they did find a slightly elevated risk of autism and several other disorders arising from ovulation induction and assisted insemination. 25 Similarly, a recent Swedish study found no elevated risk of autism from IVF, but it did find a significant risk from certain subtypes of IVF procedures as well as an elevated risk of intellectual disability. Both studies suggest the importance of further research on large population-level data sets. Because of the increasing use of ART as well as the increasing incidence and uncertain etiology of autism, it is important to explore whether these phenomena are associated. We assessed the possible association between ART and diagnosed autism in a 10-year cohort of California children.
