Autism Spectrum Disorder (ASD) encompasses a range of conditions that most commonly affect males and are characterized by lifelong neurodevelopmental derangements manifesting as deficiencies in social interaction, verbal and nonverbal communication, and dysfunctional interests and behavioral pattern that range from social isolation, delayed speech, and repetitious movement, to Asperger’s syndrome, characterized by higher levels of cognition and social behavior.
Over a period of about 2 decades, the incidence of diagnosed (ASD) has increased from about 1:1000 to 1:68 (according to the most recent estimates by the Centers for Disease Control and Prevention)This represents a significant increase from the prior estimate of 1:88, released in 2012. The question arises as to whether this dramatic change is due increased awareness of the condition leading to over-testing and over-diagnosis or whether it is a true epidemiologic phenomenon. Regardless, it is an undeniable fact that we who are actively involved in medically promoting reproduction are commonly confronted by prospective parents who are concerned that their age and reproductive performance could influence the risk of their offspring being affected by ASD.
The relationship between infertility treatments and ASD remains a subject of heated debate. Factors such as the effects of fertility medications, fertility procedures performed, a relationship with the cause of the infertility, maternal obesity , body mass index (BMI), maternal/paternal age, genetics and hormonal factors linked to fetal testosterone, have all been cited as possible contributing factors to the occurrence of ASD. Of interest is the recent emergence of evidence suggesting the role of an immunologic component in the development of ASD.
The question arises as to how/whether IVF itself increases the risk of ASD in resulting offspring. In 2007, a relatively large retrospective Swedish study compared intellectual impairment in babies born following IVF conceptions with controls and reported that 4% of IVF children had physical or mental problems as compared to 3% of those conceived naturally. However, this study could not confirm a cause and effect linkage between IVF could be and ASD. This study was somewhat flawed due to the fact that the IVF births reported dated back more than 30 years to a time when IVF technology was still in its infancy. Notwithstanding, the overall message was a positive and reassuring one for patients undergoing IVF treatment
Here are a few relatively established facts regarding the occurrence of ASD.
- Gender: ASD is more common in male offspring.
- Obstetrical History: ASD is more common in first born babies, in multiple births, in premature and small-for-gestational-age babies, following antepartum bleeding and fetal distress, as well as following birth asphyxia or trauma
- The mother’s age: The incidence of ASD increases with advancing age of the mother In fact, women over age 40Y are 51% more likely than women aged 25-29 to have a child with ASD.
- The father’s age: Traditionally, the negative effect of an advancing “biological clock” on reproduction has been linked to women, with the question of the effect of the man’s advancing age being largely ignored. But now, a recent study published in “Nature” suggests that the risk of ASD (and perhaps also schizophrenia ) increases as the age of the father progresses. When the man is under 35 years of age, the risk of ASD is 1:100, while when he is over 50Y, the incidence doubles to 1:50.
Several recent studies indicaten that certain genetic mutations shown to be implicated in ASD are four times more likely to originate in the sperm than in the egg. This is probably explained by the fact that unlike women, who are born with a lifelong component of eggs, there is a 3-monthly turnover in the generation of sperm. During the process of spermatogenesis, dividing precursor cells are easily susceptible to acquiring new mutations with each successive division. The fact that occurence of conditions such as ASD (and schizophrenia) can be influenced by a man’s age is likely to change the reproductive conversation, pushing it more into the mainstream. The time has come for men to recognize that it is not only women that should be worried about unduly putting off parenting. Hopefully, it will also prompt physicians to recommend to their male patients that they begin considering their “reproductive options” sooner rather than later and that the concept also is taught in medical schools.
- Genetics/Epigenetics: With identical twins, when one has ASD, the other is about 90% likely to also be so affected. In non-identical twins, the concordance rate is twenty times lower. This points strongly to a genetic link. There is new evidence that defects in epigenetic regulatory genes and in certain gene regions on chromosomes likely play a role in the development of autism. About 10% of ASD cases have definite links to genetic disorders such as Fragile X, neurofibromatosis and tuberous sclerosis which can often (although not easily) be detected through meticulous parental clinical history taking and can be diagnosed pre/postnataly using genetic testing, ultrasound examination and by sophisticated chromosomal and DNA analyses.
- Predicting/Diagnosing ASD: It is as yet not possible to diagnose ASD through preimplantation genetic diagnosis (PGD) or through prenatal testing. Unfortunately, only a few specific gene mutations known to be linked to autism have, as yet, been identified. But this could all change given the rapid advancement in genetic research. Recent reports have emerged of a newly found ability to isolate fetal cells from the mother’s blood, even early in pregnancy. Once sophisticated genetic testing for specific mutations evolves, it is likely that it will become possible to draw blood from the pregnant woman, isolate fetal cells, and thereby gain access to the entire fetal genome for genetic testing.
- Preventing ASD: The risk of ASD in the offspring can sometimes be reduced by the taking of folic acid supplements (4-6mg daily) for several months prior to conception. This is especially true in cases where the mother has a form of thrombophilia (a hereditary clotting disorder) associated with MTHFR pleomorphic (most particularly those associated with the C677T variant) where such pre-conceptual folic acid supplementation could be especially beneficial.