Genetic Disorders and the Fetus. Группа авторов
≥40 years had a 3.83 percent risk of chromosomal abnormality, compared with 0.56 percent in the younger age group. Other significant results were an odds ratio of 3.1 for miscarriage (1.68 percent vs. 0.42 percent) and an odds ratio of 1.66 (2.01 percent vs. 1.21 percent) for birth <34 weeks of gestation.
Paternal age
Paternal age has trended upwards in the United States, England, and elsewhere in recent years.408, 409
The current consensus view is that a male ≥40 years of age at the time of conception is defined as being of advanced age.410 Advanced paternal age (≥40) in the United States for childbearing in the 35‐ to 49‐year‐old category has risen from 42.8/1000 to 69.1/1000 from 1980–2015.411 This probably reflects increased divorce/remarriage rates and the increased use of assisted reproductive technologies.409 Advanced paternal age is associated with increased infertility and miscarriage rates,409, 412–415 as well as an increased risk of 0.3–0.5 percent of de novo autosomal dominant mutations that result in severe phenotypes.416–421 Professional societies and others whose guidelines suggest that sperm donors be less than 50 years of age,422, 423 might now reconsider given both new and established data.
Well‐established data exist for a number of autosomal dominant disorders in the offspring of older fathers408 (Table 1.4), with achondroplasia having a relative risk of 12. The causes are de novo mutations estimated to accumulate to 420 over a 20‐year period.408 An Israeli psychiatric disease registry study of 87,907 births, showed a 2.96‐fold relative risk of schizophrenia among the offspring of fathers over 50 years of age compared with those aged 20–24 years.424 A Swedish National Birth Registry study of the entire population of births (2,615,081) between 1973 and 2010 examined the link between autism and paternal age.425 The authors observed a statistically significant 3.45‐fold greater likelihood of autism for fathers age at conception of >45 years compared to fathers in the 20–24 age group. They also reported a 13.1‐fold greater likelihood of developing attention deficit hyperactivity disorder and a 2.07‐fold risk of psychosis. In a California study of 5,121 spontaneous abortions between 6 and 20 weeks of pregnancy, fathers over 50 years of age had double the likelihood of associated pregnancy loss.415 A prospective Danish study of 23,821 pregnancies showed that fathers >50 years of age had associated risks of fetal death almost twice that of younger fathers.426
Table 1.4 Single‐gene dominant disorders in offspring that are associated with advanced paternal age and relevant to prenatal diagnosis.
| Clinical condition | Gene | Population risk | Relative risk | Adjusted risk |
|---|---|---|---|---|
| Achondroplasia | FGFR3 | 1/15,000 | 12 | 1/1,250 |
| Apert syndrome | FGFR2 | 1/50,000 | 9.5 | 1/5,263 |
| Crouzon syndrome | FGFR2 | 1/50,000 | 8 | 1/6,250 |
| Pfeiffer syndrome | FGFR2 | 1/100,000 | 6 | 1/16,666 |
| Wilms tumor | WT1 | 1/10,000 | 2.1 | 1/4,761 |
| Bilateral retinoblastoma | RB1 | 1/15,000 | 5 | 1/3,000 |
| Neurofibromatosis 1 | NF1 | 1/3,000 | 2.9 | 1/1,034 |
| Osteogenesis imperfecta | COL1A1/2 | 1/10,000 | 2.5 | 1/4,000 |
| Polycystic kidney disease | PKD1/2 | 1/1,000 | 1.2 | 1/833 |
| Thanatophoric dysplasia | FGFR3 | 1/20,000 | 3.18 | 1/6,290 |
Source: Yatsenko et al.408 Reproduced with permission of Springer Nature.
A Swiss population study found that the proportion of younger fathers was uniformly different between those with and without Down syndrome offspring. Young fathers had an almost twofold increased odds for siring a child with trisomy 21.427 The authors stated the need for confirmation of their findings.
Paternal age should garner more attention during genetic counseling,428 especially with the availability of molecular analysis of multiple genes susceptible to de novo mutations in both noninvasive prenatal testing (see Chapter 8) and prenatal diagnosis (see Chapter 14).
A previous fetus or child with a genetic disorder
A genetic evaluation and counseling are usually indicated when a previous fetus or child has or had a genetic disorder, unless the matter is straightforward (e.g. previous trisomy 21) and the obstetrician is well informed. Careful inquiry should be made about the health status of a previous child. Failure or delay in the diagnosis of a monogenic disorder leaves the parents without the option of prenatal diagnosis in a subsequent pregnancy. In addition, it deprives them of the option of preimplantation genetic testing for those disorders with known mutations. Failure to make an early diagnosis of a genetic disorder during the first 5 years of life is common. For example, the Rotterdam Clinical Genetics Group reported that 50 percent of children affected by neurofibromatosis had been treated for related symptoms before a specific diagnosis had been made.429 Such delay has become problematic given that the NF1 gene and genes for many other monogenic disorders are routinely sequenced for a precise diagnosis.
Frequently, distressed parents will select a different physician for a subsequent pregnancy and a new or more recent insight may shed light on the cause of the previous disorder. For example, confined placental mosaicism (see Chapter 4) may now serve to explain the discrepancy between reported chromosomal findings at the time of CVS and fetal tissues obtained at elective abortion. Confined placental mosaicism may also be associated with intrauterine growth restriction (see Chapter