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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	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, 76} Indeed, a study of 173,687 malformed infants and 11.7 million unaffected controls, when focused on maternal smoking, yielded significant odds ratios up to 1.5 for a wide range of major congenital malformations in the offspring of smoking mothers.⁷⁷ Young nulliparous women have an increased risk of bearing a child with gastroschisis, those between 12 and 15 years of age having a more than fourfold increased risk.⁷⁸ A Californian population‐based study (1995–2012) recorded a prevalence for gastroschisis of 2.7 cases per 10,000 livebirths.⁷⁵

The surveillance system of the National Network of Congenital Anomalies of Argentina reported a 2009–2016 study of 1,663,610 births with 702 born with limb reduction defects.⁷⁹ The prevalence was 4.22/10,000 births. In 15,094 stillbirths, the prevalence rose to 30.80/10,000. A Chinese study of 223 newborn deaths in a neonatal intensive care unit noted that 44 (19.7 percent) had a confirmed genetic disorder.⁸⁰ The National Perinatal Epidemiology Centre in Ireland in a study of fatal fetal anomalies recorded 2,638 perinatal deaths, 939 (36 percent) having a congenital anomaly, 43 percent of which were chromosomal.⁸¹ More than a single anomaly was noted in 36 percent (333 of 938) of their cases. These numbers led to a significant genetic disease burden and have accounted for 28–40 percent of hospital admissions in North America, Canada, and England.^82–84 Notwithstanding their frequency, the causes of about 60 percent of congenital malformations remain obscure.^{85, 86}

The effect of folic acid supplementation, via tablet or food fortification, on the prevalence of neural tube defects (NTDs), is now well known to reduce the frequency of NTDs by up to 70 percent^{87, 88} (see Chapter 10). A Canadian study focused on the effect of supplementation on the prevalence of open NTDs among 336,963 women. The authors reported that the prevalence of open NTDs declined from 1.13 in 1,000 pregnancies before fortification to 0.58 in 1,000 pregnancies thereafter.⁸⁹

In a population‐based cohort study by the Metropolitan Atlanta Congenital Defects Program, the risk of congenital malformations was assessed among 264,392 infants with known gestational ages, born between 1989 and 1995. Premature infants (<37 weeks of gestation) were found to be more than twice as likely to have been born with congenital malformations than infants at term.⁹⁰ In a prospective study of infants weighing 401–1,500 g between 1998 and 2007, a congenital malformation was noted in 4.8 percent of these very low birthweight infants. The mean gestational age overall was 28 weeks and the mean birthweight was 1,007 g.⁹¹ A surveillance study of births, stillbirths, and fetuses for malformations in a single center with 289,365 births over 41 years noted 7,020 (2.4 percent) with one or more congenital abnormalities.⁹² Twins have long been known to have an increased rate of congenital anomalies. A UK study of 2,329 twin pregnancies (4,658 twins) and 147,655 singletons revealed an anomaly rate of 405.8 per 10,000 twins versus 238.2 per 10,000 singletons (relative risk [RR] 1.7).⁹³ The prevalence rate of anomalies among known monochorionic twins (633.6 per 10,000) was nearly twice that found in dichorionic twins (343.7 per 10,000) (RR 1.8). A California Twin Registry study of 20,803 twin pairs found an overall prevalence of selected anomalies of 38 per 1,000 persons.⁹⁴

The frequency of congenital defects is also influenced by the presence or absence of such defects in at least one parent. A Norwegian Medical Birth Registry population‐based cohort study of 486,207 males recorded that 12,292 (2.53 percent) had been born with a congenital defect.⁹⁵ Among the offspring of these affected males, 5.1 percent had a congenital defect, compared with 2.1 percent of offspring of males without such defects (RR 2.4). Ethnicity, too, has a bearing on the prevalence of cardiovascular malformations. In a New York State study of 235,230 infants, some 2,303 were born with a cardiovascular malformation. The prevalence among non‐Hispanic white (1.44 percent) was higher than in non‐Hispanic black individuals (1.28 percent).⁹⁶ However, racial/ethnic disparities clearly exist for different types of congenital defects.⁹⁷

Congenital hypothyroidism is associated with at least a fourfold increased risk of congenital malformations, and represents yet another factor that may influence incidence/prevalence rates of congenital anomalies and neurodevelopment.^{98, 99} A French study of 129 infants with congenital hypothyroidism noted that 15.5 percent had associated congenital anomalies.¹⁰⁰ Nine of the infants had congenital heart defects (6.9 percent).

Women with epilepsy on anticonvulsant medications have an increased risk of having offspring with congenital malformations, noted in one study as 2.7‐fold greater than those without epilepsy.¹⁰¹ A Cochrane Epilepsy Group Registry meta‐analysis of 31 studies of pregnant women on anticonvulsants concluded with increased, but variable RR of congenital malformations of 2.01–5.69, the latter figure being for valproate.¹⁰²

There have been reports of an increased risk of congenital malformations following the use of assisted reproductive technology (ART) and negated by other studies.¹⁰³ A 2018 report using a Centers for Disease Control and Prevention (CDC) database of 11,862,780 livebirths (2011–2013) retrospectively analyzed the 71,050 pregnancies conceived by ART. Infants conceived by ART had an increased risk (77/10,000 vs. 25/10,000), an OR of 2.14.¹⁰³ The cause(s) of this increase – whether due to the ART or the patients' genetic predisposition – remains to be determined.

Lupo et al.¹⁰⁴ in a population‐based registry study of over 10 million children in the United States assessed the association of cancer and congenital malformations. They reported that compared to children without congenital anomalies:

 children with chromosomal anomalies (n = 539,567) were 11.6 times more likely to be diagnosed with cancer and

 children with nonchromosomal congenital anomalies were 2.5 times more likely to have cancer before 18 years of age.