Genetic Disorders and the Fetus. Группа авторов

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	532.4	0.05
Chromosomal	1,845.4	0.18
Multifactorial	46,582.6	4.64
Genetic unknown	1,164.2	0.12
Total	53,175.3	5.32 a
B
All congenital anomalies 740–759 b	52,808.2	5.28
Congenital anomalies with genetic etiology (included in section A)	26,584.2	2.66
C
Disorders in section A plus those congenital anomalies not already included	79,399.3	7.94

      ^a Sum is not exact owing to rounding.

      ^b International Classification of Disease numbers.

      Source: Blencowe et al. 2018.³⁴ With permission from Elsevier.

At least 3–4 percent of all births are associated with a major congenital defect, intellectual disability, or a genetic disorder, a rate that doubles by 7–8 years of age, given later‐appearing and/or later‐diagnosed genetic disorders.^{36, 37} If all congenital defects are considered, Baird et al.³³ estimated that 7.9 percent of liveborn individuals have some type of genetic disorder by about 25 years of age. These estimates are likely to be very low given, for example, the frequency of undetected defects such as bicuspid aortic valves that occur in 1–2 percent of the population.³⁸ The bicuspid aortic valve is the most common congenital cardiac malformation and in the final analysis may cause higher mortality and morbidity rates than all other congenital cardiac defects.³⁹ About 27 percent suffer cardiovascular complications requiring surgery.^{40, 41} Mitral valve prolapse affects 2–3 percent of the general population, involving more than 176 million people worldwide.⁴² A Canadian study of 107,559 patients with congenital heart disease reported a prevalence of 8.21 per 1,000 livebirths, rising to an overall prevalence of 13.11 per 1,000 in adults.⁴³ The authors concluded that adults now account for some two‐thirds of the prevalence of congenital heart disease. Categorical examples of factors associated with an increased risk of congenital heart disease or malformations in the fetus are shown in Box 1.1. A metropolitan Atlanta study (1998–2005) showed an overall prevalence of 81.4 per 10,000 for congenital heart disease among 398,140 livebirths,⁴⁴ similar to a Belgian study of 111,225 live and stillborn infants ≥26 weeks of gestation with an incidence of 0.83 percent, chromosome abnormalities excluded.⁴⁵ A EUROCAT registry study found an increasing prevalence of severe congenital heart defects (single ventricle, atrioventricular septal defects, and tetralogy of Fallot) possibly due to increasing obesity and diabetes.⁴⁶ In a study of 8,760 patients with autism spectrum disorders and 26,280 controls, a statistically significant increase in the odds of concurrent congenital heart disease (odds ratio [OR] 1.32) was noted.⁴⁷ Atrial septal defects and ventricular septal defects were most common.

Incidence/prevalence rates of congenital defects are directly influenced by when and how diagnoses are made. Highlighting the importance of how early a diagnosis is made after birth, the use of echocardiography, and the stratification of severity of congenital heart defects, Hoffman and Kaplan⁴⁸ clarified how different studies reported the incidence of congenital heart defects, varying from 4 in 1,000 to 50 in 1,000 livebirths. They reported an incidence of moderate and severe forms of congenital heart disease in about 6 in 1,000 livebirths, a figure that would rise to at least 19 in 1,000 livebirths if the potentially serious bicuspid aortic valve is included. They noted that if all forms of congenital heart disease (including tiny muscular ventricular septal defects) are considered, the incidence increases to 75 in 1,000 livebirths.

      The newer genetic technologies, including chromosomal microarray, whole‐exome sequencing, next‐generation sequencing, and whole‐genome sequencing, have helped unravel the causes of an increasing number of isolated or syndromic congenital heart defects.^{49, 50} Identified genetic causes include monogenic disorders in 3–5 percent of cases, chromosomal abnormalities in 8–10 percent, and copy number variants in 3–25 percent of syndromic and 3–10 percent of isolated congenital heart defects.^{49, 51} A next‐generation sequencing study indicated that 8 percent and 2 percent of cases were due to de novo autosomal dominant and autosomal recessive pathogenic variants, respectively.⁵²

      Pregestational diabetes in 775 of 31,007 women was statistically significantly associated with sacral agenesis (OR 80.2), holoprosencephaly (OR 13.1), limb reduction defects (OR 10.1), heterotaxy (12.3), and severe congenital heart defects (OR 10.5–14.9).⁵³

      Maternal obesity is associated with an increased risk of congenital malformations.^54–65 The greater the maternal body mass index (BMI), the higher the risk, especially for congenital heart defects,^{59, 60, 62, 65} with significant odds ratios between 2.06 and 3.5. In a population‐based case–control study, excluding women with preexisting diabetes, Block et al.⁶⁶ compared the risks of selected congenital defects among obese women with those of average‐weight women. They noted significant odds ratios for spina bifida (3.5), omphalocele (3.3), heart defects (2.0), and multiple anomalies (2.0). A Swedish study focused on 1,243,957 liveborn singletons and noted 3.5 percent with at least one major congenital abnormality.⁶⁴ These authors used maternal BMI to estimate risks by weight. The risk of having a child with a congenital malformation rose steadily with increasing BMI from 3.5 percent (overweight) to 4.7 percent (BMI ≥40). Our own^{67, 68} and other studies⁶⁹ have implicated the prediabetic state or gestational diabetes as contributing to or causing the congenital anomalies in the offspring of obese women. In this context, preconception bariatric surgery seems not to reduce the risks of congenital anomalies.^{61, 70–72} It appears that folic acid supplementation attenuates but does not eliminate the risk of spina bifida when associated with diabetes mellitus⁷³ or obesity⁷⁴ (see Chapter 10). In contrast, markedly underweight women reportedly have a 3.2‐fold increased risk of having offspring with gastroschisis,⁷⁴ in all likelihood due to smoking and other acquired exposures.^75,