Genetic Disorders and the Fetus. Группа авторов

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.

Congenital malformations and infant morbidity and mortality

      The leading cause of infant death in the United States in 2014 was congenital malformations, deformations, and chromosomal abnormalities, accounting for 20.4 percent of 4,748 total infant deaths.¹³ Survival is clearly dependent on the severity or lethality of the congenital defect. The CDC assessed mortality rates for infants born with trisomy 13 and trisomy 18. The authors identified 5,515 infants born with trisomy 13 and 8,750 born with trisomy 18. The median age at death for both trisomy 13 and trisomy 18 was 10 days. Survival to at least 1 year occurred in 5.6 percent of those born with trisomy 13 or trisomy 18.¹⁰⁵ An international registry study (2019) from 18 countries revealed prevalence rates of 0.55 and 1.07 per 10,000 births for trisomies 13 and 18, respectively. Death in the first week of life occurred in 45 percent and 42 percent for trisomy 13 and trisomy 18, respectively. Reported mortality rates were 87 percent and 88 percent at 1 year for each of these trisomies.¹⁰⁶ A regional study in the Netherlands noted lethal congenital malformations in 51 percent of stillbirths and 70 percent among those who died during the neonatal period.¹⁰⁷ A Scottish study focusing on the survival of 6,153 infants with congenital anomalies up to the age of 5 years noted the following survival rates: chromosomal anomalies (48 percent), NTDs (72 percent), respiratory system anomalies (74 percent), congenital heart disease (75 percent), nervous system anomalies (77 percent) and Down syndrome (84 percent).¹⁰⁸ The survival rate among males with congenital defects was 84 percent, compared with 97 percent in those born unaffected.³⁰ Liu et al.¹⁰⁹ examined temporal changes in fetal and infant deaths caused by congenital malformations in Canada, England, Wales, and the United States. They concluded that the major factor responsible for the accelerated decline in infant deaths was prenatal diagnosis and elective abortion of fetuses with abnormalities. Given the frequency of Down syndrome, a more detailed discussion follows.

      Down syndrome

      The availability of prenatal diagnosis and maternal serum screening for chromosomal abnormalities has also affected the birth frequency of Down syndrome. One French study of the impact of prenatal diagnosis over a 21‐year period (1979–1999) in a well‐defined population showed a drop of 80 percent in the birth prevalence