History of recurrent spontaneous abortion
In vitro fertilization
Incidence and severity of prematurity
Infertility
Intracytoplasmic sperm injection
Later manifestation or onset of disorder
Maternal age
Maternal alcohol abuse
Maternal diabetes and gestational diabetes
Maternal diet
Maternal epilepsy, lupus erythematosus and other illnesses
Maternal fever or use of hot tub in the first 6 weeks of pregnancy
Maternal folic acid supplementation
Maternal grandmother's age
Maternal obesity
Maternal serum screening for chromosome abnormalities
Maternal smoking
Maternal‐specific susceptibility genes
Maternal use of medication
Mortality rates decreasing
Multiple pregnancy rate
Necropsy
Noninvasive prenatal testing using cell‐free fetal DNA for chromosomal abnormalities and monogenic disorders
Parent with a congenital abnormality or genetic disorder
Paternal age
Previous affected child
Previous maternal immunization/vaccination
Season of the year
Training and expertise in examination of newborns
Use of chromosomal analysis
Use of chromosomal microarray
Use of whole‐exome sequencing
Use of whole‐genome sequencing
Use of death certificates
Use of registry data
Incidence and prevalence of genetic disorders and congenital malformations
Estimates of aneuploidy in oocytes and sperm reach 25 percent and 3–4 percent, respectively.14, 15 Estimates, especially for oocytes, vary widely (see Chapter 2). The effect of maternal age, among other factors, is important. At 25 years, early thirties, and >40 years of age, the rate of aneuploidy approximates 5 percent, 10–25 percent, and 50 percent, respectively.15–19 Estimates of aneuploidy and structural chromosomal abnormalities in sperm vary from 7 to 14 percent.20 Not surprisingly, then, about one in 13 conceptions results in a chromosomally abnormal conceptus,21 while about 50 percent of first‐trimester spontaneous abortions are associated with chromosomal anomalies.22 One study of blastocysts revealed that 56.6 percent were aneuploid. Moreover, these blastocysts produced in vitro from women of advanced maternal age also revealed mosaicism in 69.2 percent.23 Similar results have been reported by others.24 Clinically significant chromosomal defects occur in 0.65 percent of all births; an additional 0.2 percent of babies are born with balanced structural chromosome rearrangements that have implications for reproduction later in life (see Chapters 11 and 13). Between 5.6 and 11.5 percent of stillbirths and neonatal deaths have chromosomal defects.25
Congenital malformations with obvious structural defects are found in about 2 percent of all births.26 This was the figure in Spain among 710,815 livebirths,27 with 2.25 percent in Liberia,28 2.03 percent in India,29 and 2.53 percent among newborn males in Norway.30 The Mainz Birth Defects Registry in Germany in the 1990–1998 period reported a 6.9 percent frequency of major malformations among 30,940 livebirths, stillbirths, and abortions.31 Pooled data from 12 US population‐based birth defects surveillance systems, which included 13.5 million livebirths (1999–2007), revealed that American Indians/Alaska natives had a ≥50 percent greater prevalence for seven congenital malformations (including anotia or microtia, cleft lip, trisomy 18, encephalocele, limb‐reduction defect).32 Factors that had an impact on the incidence/prevalence of congenital malformations are discussed later.
Over 25,500 entries for genetic disorders and traits have been catalogued.2 Estimates based on 1 million consecutive livebirths in Canada suggested a monogenic disease in 3.6 in 1,000, consisting of autosomal dominant (1.4 in 1,000), autosomal recessive (1.7 in 1,000), and X‐linked recessive disorders (0.5 in 1,000).33 Baseline birth prevalence of rare single‐gene disorders for multiple countries are shown in Figure 1.1, which highlights the contribution of consanguinity‐associated disorders.34 Polygenic disorders occurred at a rate of 46.4 in 1,000 (Table 1.1). A key study of homozygosity in consanguineous patients with an autosomal recessive disease showed that, on average, 11 percent of their genomes were homozygous.35 Each affected individual had 20 homozygous segments exceeding 3 cM.
Figure 1.1 Total baseline birth prevalence of rare single‐gene disorders by World Health Organization (WHO) region, highlighting the important contribution of consanguinity to monogenic disorders.
Source: Blencowe et al. 2018.34 Reproduced with permission from Springer.
Table 1.1 The frequencies of genetic disorders in 1,169,873 births, 1952–198334.
| Category | Rate per million livebirths | Total births (percent) |
|---|---|---|
| A | ||
| Dominant | 1,395.4 | 0.14 |
| Recessive | 1,665.3 | 0.17 |
| X‐linked |
