In the combined data from several small series, on a total of 510 chromosomally normal fetuses with increased nuchal translucency, there were 77 (15%) with defects (Table 1)^3–21.

The most commonly seen defects were anencephaly (n = 1), macrocephaly (n = 1), spina bifida (n = 2), holoprosencephaly (n = 1), Dandy–Walker malformation (n = 1), facial cleft (n = 2), agnathia (n = 1), cystic hygromas (n = 1), cardiac defects (n = 17), pentalogy of Cantrell (n = 1), Ivemark syndrome (n = 1), Toriello–Carey syndrome (n = 1), diaphragmatic hernia (n = 2), esophageal atresia (n = 1), duodenal atresia (n = 1), exomphalos (n = 4), megacystis (n = 3), multicystic kidneys (n = 1), polycystic kidneys (n = 3), amnion rupture sequence (n = 1), body stalk anomaly (n = 2), achondrogenesis (n = 1), achondroplasia (n = 2), campomelic dysplasia (n = 1), ectrodactyly-ectodermal dysplasia–cleft palate syndrome (EEC) (n = 1), fetal akinesia deformation sequence (FADS) (n = 3), syringomyelia (n = 1), kyphosis (n = 1), talipes (n = 1), GM1-gangliosidosis (n = 1), Joubert syndrome (n = 1), Meckel–Gruber syndrome (n = 1), myotonic dystrophy (n = 1), Noonan syndrome (n = 5), spinal muscular atrophy (n = 2), Zellweger syndrome (n = 1) and unspecified syndromes (n = 6).

In the multicenter screening project for trisomy 21 by a combination of maternal age and fetal nuchal translucency involving about 100,000 pregnancies¹, there were 4116 singleton, chromosomally normal pregnancies with fetal nuchal translucency above the 95th centile for crown–rump length²². This study includes data on the first 565 cases reported by Pandya et al.²³ and those on 89 cases which had detailed postnatal follow up²⁴. A wide range of structural defects and genetic syndromes were identified in 161(3.9%) of the cases (Table 2)²².

The patients were subdivided according to nuchal translucency thickness into five groups: 95th centile to 3.4 mm, 3.5–4.4 mm, 4.5–5.4 mm, 5.5–6.4 and equal to or greater than 6.5 mm. The prevalence of fetal abnormalities increased with nuchal translucency thickness: 3 mm, 2.4%; 4 mm, 7.1%; 5 mm, 12.3%; 6 mm, 16.7%; 7 mm 35.6% (Table 2)²². The diagnosis of abnormalities was made by ultrasound examination in mid-pregnancy, or by pathological examination in terminations of pregnancy and intrauterine or neonatal deaths, or by clinical examination and appropriate investigations in live births. In these calculations, we did not include minor defects, such as choroid plexus cysts, pyelectasia, digital abnormalities or cardiac defects that would not require therapy²².

An increasing number of fetal abnormalities can now be diagnosed by ultrasound examination in early pregnancy. A review of the literature for studies reporting the diagnosis of fetal abnormalities at the 11–14-week scan identified several conditions that were associated with increased nuchal translucency thickness (Table 4)^25–57.

Increased nuchal translucency at the 11–14-week scan is associated with a wide range of fetal abnormalities. The observed prevalence for some of the abnormalities, such as anencephaly, holoprosencephaly, microcephaly, facial cleft, gastroschisis, renal abnormalities, bowel obstruction and spina bifida, may not be different from that in the general population. However, the prevalence of major cardiac defects, diaphragmatic hernia, exomphalos, body stalk anomaly and fetal akinesia deformation sequence appears to be substantially higher than in the general population and it is therefore likely that there is an association between these abnormalities and increased nuchal translucency thickness. Similarly, there may well be an association between increased translucency and a wide range of rare skeletal dysplasias and genetic syndromes that are usually found in less than 1 in 10,000 pregnancies; however, the number of affected cases, both in the present and previous series of fetuses with increased nuchal translucency, is too small for definite conclusions to be drawn.

In addition to the association between increased nuchal translucency thickness and a wide range of fetal abnormalities, the rates of miscarriage and perinatal death increase with nuchal translucency thickness. These data would be useful in counselling parents of affected pregnancies and in alerting sonographers to plan the appropriate follow-up investigations for such pregnancies. However, it should be emphasized to the parents that increased nuchal translucency thickness per se does not constitute a fetal abnormality and, once chromosomal defects have been excluded, about 90% of pregnancies with fetal translucency below 4.5 mm would result in healthy live births; the rates for translucency of 4.5–6.4 mm and 6.5 mm or more are about 80% and 45%, respectively²².

Increased nuchal translucency is of particular importance in its association with major abnormalities of the heart and great arteries. Studies involving pathological examination in both chromosomally abnormal and normal fetuses with increased nuchal translucency at 11–14 weeks have demonstrated a high prevalence of abnormalities of the heart and great arteries^58–63. Additionally, there are several case reports or small series on the sonographic diagnosis of cardiac defects at the 11–14-week scan; in a total of 21 fetuses with major cardiac defects, 17 (81%) had increased nuchal translucency^25–28. Furthermore, a retrospective study of 1389 chromosomally normal fetuses with increased translucency reported that the prevalence of major cardiac defects increased with translucency thickness; the diagnosis of cardiac defects was made by ultrasound examination in mid-pregnancy, or by pathological examination in terminations of pregnancy and intrauterine or neonatal deaths, or by clinical examination and appropriate investigations in livebirths⁶³.

In The Fetal Medicine Foundation Project (Table 2), the prevalence of major abnormalities of the heart and great arteries was 10 per 1000 and increased exponentially with increasing translucency thickness from about 4 per 1000 for translucency of 95th centile–3.4 mm, 27 per 1000 for translucency of 3.5–4.4 mm, 43 per 1000 for translucency of 4.5–5.4 mm, 63 per 1000 for translucency of 5.5–6.4 mm, and 169 per 1000 for translucency equal to or greater than 6.5 mm²².

A retrospective study of 29 154 chromosomally normal singleton pregnancies identified major defects of the heart and great arteries in 50 cases (these included 18 that were diagnosed antenatally by an ultrasound examination at 16–31 weeks of gestation, 13 that were diagnosed at pathological examination following intrauterine death or termination of pregnancy for conditions other than cardiac defects, and 19 that were diagnosed in live births)⁶⁴. The prevalence of major cardiac defects increased with nuchal translucency thickness from 0.8 per 1000 for those with translucency below the 95th centile to 63.5 per 1000 for translucency above the 99th centile (Table 6)⁶⁴.

This is a sporadic defect with a birth prevalence of about 1 in 4000. In about 50% of affected fetuses, there are associated chromosomal abnormalities or other defects. In those with isolated diaphragmatic hernia, survival after postnatal surgery is about 50%, but the remainder die due to pulmonary hypoplasia and pulmonary hypertension⁶⁹.

This autosomal dominant syndrome has a birth prevalence of about 1 in 26,000, but the majority of cases represent new mutations. The characteristic features include short limbs, lumbar lordosis, short hands and fingers, macrocephaly and depressed nasal bridge. Intelligence and life expectancy are normal. Prenatally, limb shortening usually becomes apparent only after 22 weeks of gestation.

In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there were two cases with the condition^13,21.

Asphyxiating thoracic dystrophy or Jeune’s syndrome is an autosomal recessive condition with a birth prevalence of about 1 in 70,000. The characteristic features are narrow chest and rhizomelic limb shortening. There is a variable phenotypic expression and, consequently, the prognosis varies from neonatal death, due to pulmonary hypoplasia, to normal survival. Limb shortening is mild to moderate and this may not become apparent until after 24 weeks of gestation.

In a case report of Jeune’s syndrome, routine ultrasound examination at 14 weeks demonstrated increased nuchal translucency (5.8 mm) and the femur length was on the 5th centile for gestation; repeat ultrasonography at 22 weeks showed a short narrow thorax and the length of all limbs was well below the 5th centile³⁴.

This is a usually sporadic and occasionally familial syndrome with a birth prevalence of about 1 in 14,000. It is characterized by macrosomia and hyperplasia and/or hypertrophy of the tongue, kidneys, adrenals, and pancreas, exomphalos and neonatal hypoglycemia and polycythemia. In some cases, there is mental handicap, which is thought to be secondary to inadequately treated hypoglycemia. About 5% of affected individuals develop tumors during childhood, most commonly nephroblastoma and hepatoblastoma.

In The Fetal Medicine Foundation Project (Table 2), one of the fetuses with increased nuchal translucency and exomphalos had Beckwith–Wiedemann syndrome²².

This is a rare, lethal, autosomal recessive skeletal dysplasia characterized by severe shortening of all long bones, increased bone density, small oral cavity with protuberant tongue and hemosiderosis of the liver.

In a case report of a 12-week fetus with the syndrome, from a high-risk pregnancy, there was shortening of all limbs, narrow chest and increased nuchal translucency (6.3mm); after termination of the pregnancy, pathological examination demonstrated thickening of periostal bone of the metaphyses and diaphyses and hemosiderosis of the liver³⁵.

This lethal, sporadic abnormality, characterized by the presence of a major abdominal wall defect, severe kyphoscoliosis and a rudimentary umbilical cord, has a birth prevalence of about 1 in 15,000. The pathogenesis is uncertain but possible causes include abnormal folding of the trilaminar embryo during the first 4 weeks of development, early amnion rupture with amniotic band syndrome, and early generalized compromise of embryonic blood flow.

In the studies on chromosomally normal fetuses with increased nuchal translucency (Table 1 and Table 2), the prevalence of body stalk anomaly (12 in 4626) was higher than that expected in the general population^11,13,22. In a screening study involving ultrasound examinations at 11–14 weeks and 18–20 weeks of gestation in 3991 patients, there were two cases of body stalk anomaly and they were both diagnosed at the early scan; in one of the cases, there was increased nuchal translucency thickness¹³.

This is a rare, lethal, autosomal recessive syndrome characterized by shortening and bowing of the lower limbs, growth deficiency of prenatal onset, large calvarium with disproportionately small face and narrow chest. Some of the affected genetically male individuals show a female phenotype. Patients usually die in the neonatal period from pulmonary hypoplasia.In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there was one case with the condition⁶.

This is a rare autosomal dominant condition with a wide variability in phenotypic expression. It is characterized by ectrodactyly (split hand and foot), facial cleft (lip and/or palate) and ectrodermal dysplasia (anomalies of hair, teeth, nails, nasolacrimal ducts and sweat glands).

In the studies reporting on chromosomally normal fetuses with increased nuchal translucency (Table 1), there was one case with the condition¹⁴. Additionally, there is one case report of EEC syndrome presenting with increased nuchal translucency, oligodactyly and umbilical cord cyst at 14 weeks; after termination of pregnancy, pathological examination demonstrated coarctation of the aorta³⁷. There is another case report on the early diagnosis of the syndrome, but the study does not comment on nuchal translucency measurement; routine ultrasound examination at 14 weeks demonstrated lobster-claw deformities of the hands and feet and facial clefting⁷² . Pathological examination after termination of the pregnancy confirmed the diagnosis. Subsequently, examination of the parents demonstrated no physical abnormalities, but the mother had microdontia of the lateral upper incisors which were crowned at the age of 15 years⁷².

This is a heterogeneous group of conditions resulting in multiple joint contractures, including bilateral talipes and fixed flexion or extension deformities of the hips, knees, elbows and wrists. This sequence includes congenital lethal arthrogryposis, multiple pterygium and Pena–Shokeir syndromes. Pathological studies have reported that these features are frequently associated with fetal myopathy, neuropathy or an underlying connective tissue abnormality. Prenatal diagnosis is usually made by ultrasonography during the second or third trimesters of pregnancy and is based on the demonstration of the skeletal deformities; in about one-quarter of the cases, there is nuchal edema³⁸.

In the studies on chromosomally normal fetuses with increased nuchal translucency (Table 1 and Table 2), the prevalence of FADS (nine in 4626) was higher than that expected in the general population^8,17,22. A case report of a 12-week fetus in a woman with a previous pregnancy affected by FADS reported akinesia, extention of the hips and flexion of the knees; the study did not comment on the measurement of nuchal translucency⁷³.

This is a usually lethal autosomal recessive disorder with a birth prevalence of about 1 in 15,000. It is characterized by the presence of diaphragmatic hernia, digital defects, coarse face and short webbed neck.

This is a rare, lethal, autosomal recessive condition characterized by hydrocephalus, absent corpus callosum, facial cleft, micrognathia, polydactyly, talipes and cardiac septal defects. The brain hemispheres lie separated from each other at the bottom of the skull and the lateral ventricles open medially into the fluid-filled space between and on the top of the hemispheres.

Ammala and Salonen⁴¹ reported the ultrasound diagnosis at 12 weeks in a high-risk pregnancy from Finland, where the condition may be more common. There were abnormal brain structures with mid-line echoes only at the bottom of the skull and a large cyst in the upper posterior part of the brain and talipes; in addition, there was increased nuchal translucency⁴¹. In another non-Finnish family at high risk for this syndrome, ultrasound examination at 11 weeks demonstrated increased nuchal translucency, a keyhole defect of the skull in the occipital region and talipes⁴².

This is a heterogeneous disorder that is characterized by vertebral and rib abnormalities. An autosomal recessive type (spondylothoracic dysplasia) is characterized by a constricted, short thorax and lethal respiratory insufficiency in infancy. Another type (spondylocostal dysplasia), in which most cases are autosomal recessive but a few are autosomal dominant, is associated with survival to adult life but with some degree of physical disability. In this type, there are other abnormalities, such as caudal agenesis and diaphragmatic hernia.

This is a rare, lethal, autosomal recessive condition characterized by partial or complete absence of the cerebellar vermis. It is associated with profound mental retardation and developmental delay. Death usually occurs in the first 5 years of life.

This lethal, autosomal recessive condition, with a birth prevalence of about 1 in 10,000, is characterized by the triad of encephalocele, bilateral polycystic kidneys and polydactyly.

This is a very rare, autosomal recessive syndrome characterized by short limbs, vertebral abnormalities, deafness and flat face with depressed nasal bridge. Intelligence and life expectancy are normal.

This is an autosomal dominant condition with wide variability in expression but about 50% of cases represent new mutations. The birth prevalence is about 1 in 2000. It is characterized by lymphedema, thought to be due to dysplasia of the lymphatic system, short and webbed neck, short stature, heart defects, most commonly pulmonary valve stenosis, shield chest, hypertelorism and low set ears. Life expectancy is probably normal in those individuals without severe heart disease. Mild mental retardation is present in about one-third of cases.

This is a lethal skeletal dysplasia with a birth prevalence of about 1 in 60,000. The majority of cases are new mutations of the genes encoding for polypeptide chains 1 and 2 of collagen type I. Recurrence (6–7%) is usually due to parental mosaicism (somatic or germ-line), although, in a small number of families, autosomal recessive inheritance has been observed⁷⁴. In the second trimester, the characteristic sonographic features are short limbs and ribs with multiple fractures and hypomineralization of the skull. Death occurs either prenatally or shortly after birth because of respiratory failure. In high-risk pregnancies, prenatal diagnosis can be made by chorionic villus sampling and DNA analysis or demonstration of abnormal collagen production by cultured fibroblasts.

This is a rare, autosomal recessive condition characterized by macrosomia, nephromegaly and depressed nasal bridge. The condition is similar to Beckwith–Wiedemann syndrome but they differ in their facial features. Fetal and neonatal mortality is more than 60% and, in survivors, there is a high incidence of neurodevelopmental delay.

This is a rare, autosomal recessive condition characterized by symmetrical limb defects of variable severity (tetraphocomelia), facial cleft, hypertelorism, microcephaly and growth retardation. The condition is associated with the cytogenetic finding of premature centromere separation and puffing.

This is a rare, autosomal recessive, lethal skeletal dysplasia, characterized by short limbs, narrow thorax and post-axial polydactyly. Associated anomalies are frequently found, including congenital heart disease, polycystic kidneys and intestinal atresia. Four different types have been recognized. Type I (Saldino–Noonan) has narrow metaphyses; type II (Majewski) has cleft lip and palate and disproportionally shortened tibiae; type III (Naumoff) has wide metaphyses with spurs; type IV (Beemer–Langer) is characterized by median cleft lip, small chest with extremely short ribs, protuberant abdomen with umbilical hernia and ambiguous genitalia in some 46,XY individuals.

This is an autosomal recessive condition with a birth prevalence of about 1 in 20,000. It is associated with a high perinatal and infant mortality. The features include severe mental retardation, characteristic minor facial anomalies, cleft palate, polydactyly and syndactyly, cardiac defects and, in the male, ambiguous or female external genitalia, and deficiency of the enzyme 7-dehydrocholesterol reductase.

This is a lethal, autosomal recessive condition with a birth prevalence of about 1 in 25,000. It is characterized by degeneration of anterior horn cells of the spinal cord and brain stem with subsequent muscular hypotonia and atrophy. The onset of symptoms may be intrauterine with a decrease in fetal movements. Death, which occurs in the first 2 years of life, is usually due to respiratory failure.

This is a sporadic condition with a birth prevalence of about 1 in 10,000. The term derives from the Greek, meaning death-bearing. It is characterized by severe shortening of the limbs which are bowed, narrow thorax with short ribs and enlarged head with prominent forehead; in some cases, there is a cloverleaf skull. The condition is lethal, usually in the neonatal period.

This is an extremely rare, autosomal recessive condition characterized by trigonocephaly, short nose, prominent maxilla, joint deformities and loose skin due to hyperelasticity. About half of the affected individuals die in infancy while survivors are severely mentally handicapped with progressive microcephaly.

The acronym VACTERL is used to describe a rare, sporadic association of defects including vertebral abnormalities, anal atresia, cardiac defects, tracheo-esophageal fistula with esophageal atresia, radial and renal defects. The prognosis of each patient depends on the particular combination and severity of the abnormalities present. Mental function is usually normal.

This lethal, autosomal recessive syndrome has a birth prevalence of about 1 in 25,000. It is characterized by absence or marked decrease in peroxisomes, resulting in profound muscular hypotonia. Other features include dolichoturricephaly, hypertelorism, cataracts, brain abnormalities, cardiac defects, hepatomegaly, and growth retardation. Death occurs in the first 2 years of life, most commonly due to chest infections and liver failure.