of the risks of CVS or amniocentesis, with the associated details related to any problems, pitfalls or reservations. Now, given the very low procedural risks, all women should be offered routine prenatal genetic studies that focus on chromosomal analysis and α‐fetoprotein (see Chapter 17). Advances in fetal imaging and low risks of fetal loss following amniocentesis (0.1–0.4 percent) or CVS (0.2–0.4 percent)404, 405 (see Chapter 9) have led to the policy change. The advent of noninvasive prenatal testing (see Chapters 6 and 7) has further decreased the need for CVS or amniocentesis.
Excluding infants with chromosome abnormalities, a prospective analysis of 102,728 pregnancies (including abortions, stillbirths, and livebirths) in Texas found that the incidence of congenital malformations increased significantly and progressively in women after 25 years of age.406 The authors found that an additional age‐related risk of nonchromosome malformations was approximately 1 percent in women 35 years of age or older. The odds ratio for cardiac defects was 3.95 in infants of women 40 years of age or older when compared with women aged 20–24 years.
Pregnancy outcomes related to maternal age were reported in a Danish study of 369,516 singleton cases.407 Pregnancies were followed from 11–14 weeks to delivery or termination and the age groups (20–34, 35–39, and ≥40 years) compared. Adverse outcomes included chromosomal abnormalities, congenital malformations, miscarriage, stillbirth, and delivery prior to 34 weeks of gestation. Women ≥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
