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