Edwards Syndrome (Trisomy 18)

Literature and regulatory information updated: 4 October 2026.

Trisomy 18 (Edwards Syndrome): Guidelines for Surveillance, Diagnosis and Clinical Follow-up

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0. Initial Reference Table

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1. Introduction

Trisomy 18 was recognised as a distinct clinical entity in 1960, when three research groups almost simultaneously associated a characteristic pattern of multiple congenital malformations with an extra chromosome 18. John Hilton Edwards' Oxford group published a description in the Lancet of newborns with a reproducible constellation of abnormalities, including clenched hands, short sternum, low-set ears and marked growth retardation, linking them for the first time to an autosomal trisomy subsequently identified as chromosome 18 [16]. At virtually the same time, Klaus Patau and colleagues described another pattern of multiple congenital abnormalities caused by an extra autosome in the Lancet, corresponding to what is now termed trisomy 13 [17], while David W. Smith's team independently characterised a new autosomal trisomy syndrome with an Edwards-like phenotype in the Journal of Pediatrics [18]. "Edwards syndrome" became established in English-language literature in recognition of the first publication's author, although detailed clinical characterisation largely reflects Smith's later work and his school of dysmorphology.

This milestone occurred during rapid advances in human cytogenetics, a few years after establishment of the correct human chromosome number (46) and Jérôme Lejeune's description of trisomy 21 in 1959. Trisomy 18 thus became the second complete autosomal trisomy syndrome identifiable by routine karyotyping and remains the second most frequent among liveborn infants after trisomy 21 [3,7,8].

Over the following six decades, understanding of trisomy 18 natural history changed substantially. Clinical series from the 1990s, particularly Root and Carey and Baty and colleagues, established the classical findings of very limited survival and severe neurodevelopmental impairment that supported an almost exclusively palliative approach for decades [10,11,19]. More recent population studies, including Rasmussen and colleagues' United States work and subsequently Meyer and colleagues', more precisely documented mortality stratified by gestational age, birth weight and surgical intervention, revealing greater outcome heterogeneity than previously recognised [20,21]. Similarly, Nelson and colleagues' Ontario population cohort, published in JAMA in 2016, and Kosiv and colleagues' congenital cardiac surgery analysis, published in Pediatrics in 2017, documented long-term survival in some patients and lower hospital mortality among operated patients [22,23]. In August 2025, this development culminated in an American Academy of Pediatrics clinical report on care for infants and children with trisomy 13 and trisomy 18, explicitly recognising that these conditions should not be described as "incompatible with life" and recommending individualised shared decision-making that does not rely solely on chromosomal diagnosis [24]. The account encompasses molecular pathophysiology and systematic clinical surveillance, drawing on foundational syndrome references, Cereda and Carey's review in the Orphanet Journal of Rare Diseases [3], Kepple, Fishler and Peeples' surveillance guidelines [9], and the latest American Academy of Pediatrics clinical report [24].

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2. Molecular Genetics and Pathophysiology

Trisomy 18 results from an additional complete or partial chromosome 18 copy, producing three copies rather than the usual two in diploid cells. It is therefore an autosomal aneuploidy rather than a monogenic disorder with one causal gene and five-class ACMG (American College of Medical Genetics and Genomics) variant classification. Phenotypic severity reflects gene dosage imbalance arising from simultaneous overexpression of hundreds of chromosome 18 genes.

2.1 Free trisomy

In most cases (approximately 94%), trisomy is free and non-mosaic: all cells carry three complete chromosome 18 copies (karyotype 47,XX,+18 or 47,XY,+18), resulting from a segregation error during maternal gametogenesis [2,3,5]. Approximately 85% are maternal in origin, with a marked maternal-age effect resembling trisomy 21 [5]. Unlike other human trisomies, in which segregation errors occur more often in meiosis I, approximately 50% of oogenesis nondisjunction errors occur in meiosis II [2,3]. This mechanism is strongly associated with advanced maternal age, with mean maternal age approximately 32 at birth of a child with complete trisomy 18, reflecting the exponential increase in meiotic nondisjunction with oocyte ageing [3,7,8]. In a Brazilian series, 63% of affected fetuses had mothers older than 35 [2].

2.2 Mosaicism

A minority of cases, fewer than 5% (approximately 4%), are mosaic, with trisomic and normal euploid cell lines coexisting following a postzygotic mitotic error [2,3]. Mosaicism level, usually estimated in peripheral blood lymphocytes, may not accurately reflect trisomic cell proportions in other tissues and correlates imperfectly with clinical severity; individuals with high blood trisomic percentages may have relatively attenuated phenotypes, highlighting this genotype–phenotype correlation's limitations [3,4]. Mosaicism for an additional chromosome 18 is associated with longer survival and a spectrum from a phenotypically normal child to the complete malformation pattern [8].

2.3 Partial trisomy and translocations

A rarer third mechanism (approximately 2% of cases) is partial trisomy, generally arising from an unbalanced translocation inherited from a parent carrying a balanced reciprocal or Robertsonian translocation [2,3]. Only one chromosome 18 segment is triplicated, and phenotype depends critically on its location and extent. Isolated short-arm trisomy (18p) tends to produce a much milder, non-specific presentation, with variable and sometimes almost absent cognitive impairment; long-arm trisomy (18q), particularly involving 18q12.1 to 18q21.2, more closely reproduces the complete syndrome. This led to a proposed "critical region" whose triplication appears necessary and sufficient for most cardinal features, including severe cognitive impairment, although no single gene accounts for the entire phenotype, unlike more clearly defined contiguous gene syndromes [7]. Parental karyotyping is mandatory when a translocation is identified because finding a balanced carrier directly informs recurrence counselling for future pregnancies [3,8].

The relationship between triplicated segment and phenotype is described below [8]:

2.4 Pathophysiology

Excess chromosome 18 gene dosage disrupts multiple organogenesis processes during early embryonic and fetal development, including cardiac morphogenesis, neuronal migration and proliferation, neural tube and posterior fossa formation, and axial and appendicular skeletal development. This simultaneous multiorgan disruption explains trisomy 18's syndromic, multisystem nature, with more than 130 abnormalities described, none individually pathognomonic but collectively supporting recognition with a high index of suspicion [7,8,16,18]. Neuropathology describes pyramidal tract abnormalities, sparse myelination and microgyria [8].

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3. Clinical Spectrum and Manifestations by Organ System

The trisomy 18 phenotype comprises a reproducible constellation of dysmorphic findings and major structural malformations whose combination, rather than any single finding, supports clinical recognition.

Growth and general presentation. Fetuses and newborns typically show intrauterine growth restriction, birth weight markedly below gestational-age expectations, reduced fetal activity, polyhydramnios, a small placenta and a single umbilical artery. Mean birth weight was 2,340 g in one series [8] and 2,240 g in another, with weight, length and head circumference below the 3rd percentile and poor postnatal weight gain [5]. Gestation length is altered: approximately one third are premature and one third post-term [8]. Skeletal muscle and subcutaneous and adipose tissue hypoplasia also occur [8]. Neonatal findings include initial hypotonia followed by progressive hypertonia, weak cry, reduced sound response and marked sucking difficulty.

Craniofacial. The most consistent features include a prominent occiput with narrow bifrontal diameter, microcephaly, short palpebral fissures, low-set and often malformed ears, small mouth with a narrow palatal arch and micrognathia. Cleft lip and/or palate occur in a substantial minority. Findings in 10% to 50% include large fontanelles, hypoplastic orbital ridges, inner epicanthic folds, ptosis, corneal opacity and retinal abnormalities (folds, hypopigmentation, dysplasia, haemorrhagic areas and gliosis) [8]; the fundi are usually very pale [5]. Rarer findings (below 10%) include Wormian bones, shallow elongated sella turcica, oblique palpebral fissures, hypertelorism, iris coloboma, cataract, microphthalmia and choanal atresia [2,8].

Extremities. A particularly recognisable feature is clenched hands with the second finger overlapping the third and the fifth overlapping the fourth, associated with nail hypoplasia and often arches on six or more finger pads. Arches on all ten fingers are rarely found in other conditions; an otoscope lens without its speculum permits newborn fingerprint visualisation, although this finding is now infrequently documented [5]. Other findings include camptodactyly, absent distal fifth-finger flexion crease (with or without absent third- and fourth-finger distal creases), and nail hypoplasia particularly affecting the fifth finger and toes [5,8]. Rocker-bottom feet with a prominent calcaneus and short dorsiflexed hallux are common. Findings in 10% to 50% include ulnar or radial hand deviation, hypoplastic or absent thumb, single palmar crease, talipes equinovarus and second–third toe syndactyly; below 10%, third–fourth finger syndactyly, polydactyly, short fifth metacarpals, ectrodactyly and radial aplasia [8].

Thorax, abdominal wall and skeleton. The sternum is short with fewer ossification centres, and nipples are small; in 10% to 50%, the chest is relatively broad, with or without widely spaced nipples [8]. Chest radiographs usually show rib irregularity [5]. Inguinal or umbilical hernias, rectus diastasis, small pelvis and limited hip abduction are frequent [8]. Findings below 10% include incomplete clavicular ossification, hemivertebrae, fused vertebrae, short neck, scoliosis, rib abnormalities, pectus excavatum and hip dislocation [8].

Skin. Redundant skin, mild forehead and back hirsutism and prominent cutis marmorata; haemangiomas occur in a minority [8].

Cardiovascular. Congenital heart disease affects 45% to more than 90%, depending on the series, and is the systemic finding most consistently associated with morbidity and mortality. A clinical genetics reference review reports congenital heart disease in at least 90%, usually ventricular septal defect with or without valve dysplasia, and multivalvular dysplasia in most [5]. The most frequent defects are ventricular septal defect, patent ductus arteriosus and atrial septal defect; more complex forms, including double-outlet right ventricle, atrioventricular septal defects and hypoplastic left heart syndrome, occur in a minority but substantially affect prognosis and surgical eligibility. Multiple concurrent cardiac lesions are frequent. Findings in 10% to 50% include bicuspid aortic and/or pulmonary valves, nodular valve leaflets, pulmonary stenosis and aortic coarctation; below 10%, anomalous coronary artery, transposition of the great arteries, tetralogy of Fallot, dextrocardia, aberrant subclavian artery and arterial intimal proliferation with arteriosclerotic changes and medial calcification [8].

Respiratory. Central apnoea and respiratory failure are major early death causes. Upper airway obstruction, parenchymal lung disease and pulmonary hypertension contribute to high ventilatory support requirements during intensive care, with historically low successful extubation rates. Abnormal segmentation or absence of the right lung and diaphragmatic muscle hypoplasia with or without eventration occur in 10% to 50% [8]; congenital diaphragmatic hernia is associated with trisomy 18, which should be excluded chromosomally when this finding is detected prenatally [25].

Neurological. Alongside severe cognitive impairment, almost universal among survivors, structural central nervous system abnormalities occur, most commonly choroid plexus cysts and cerebellar hypoplasia; rarer abnormalities include Dandy–Walker malformation, neural tube defects and corpus callosum agenesis. Other abnormalities below 10% include facial palsy, sparse myelination, microgyria (polymicrogyria), hydrocephalus, pyramidal tract abnormalities and myelomeningocele [2,8]. Neurologically mediated central apnoea and seizures, reported in approximately one quarter to half of older patients and often triggered by photosensitivity, are important functional complications for survival and quality of life. Reported seizures are complex partial and generalised tonic–clonic, often difficult to control [8]; photophobia is common in surviving children [5].

Gastrointestinal and nutritional. Feeding difficulty is almost universal, arising from structural abnormalities (omphalocele, oesophageal atresia and diaphragmatic hernia, among others) and neuromuscular swallowing incoordination, with increased aspiration risk. Gastro-oesophageal reflux is very frequent [5]. Findings in 10% to 50% include Meckel diverticulum, heterotopic pancreatic and/or splenic tissue, omphalocele, incomplete colonic rotation and malpositioned or funnel-shaped anus; below 10%, hypertrophic pyloric stenosis, extrahepatic biliary atresia, hypoplastic gallbladder, gallstones, imperforate anus and tracheo-oesophageal fistula [8].

Genitourinary. Renal malformations, including horseshoe kidney, duplicated collecting system, renal dysplasia and hydronephrosis, are frequent and warrant systematic postnatal ultrasound. Ectopic kidney and polycystic kidney with small cysts are also described [8], and fetal renal lobulation is usual [5]. Cryptorchidism is frequent in males; in females, hypoplastic labia majora with a prominent clitoris occur in 10% to 50%; below 10%, hypospadias and bifid scrotum in males and bifid uterus and ovarian hypoplasia in females [8].

Endocrine. Thyroid or adrenal hypoplasia and thymic hypoplasia have been described in a minority [8].

Oncological and haematological. Trisomy 18 carries increased embryonal tumour risk, particularly hepatoblastoma and less frequently Wilms tumour, although precise epidemiological quantification remains limited [26,27]. Cereda and Carey's review counted at least eight published Wilms tumour cases (estimated risk approximately 1%) and seven hepatoblastomas [3]; Wilms tumour has occurred in long-term survivors [5]. Transient neonatal cytopenias, particularly thrombocytopenia, are also common.

Orthopaedic and otorhinolaryngological. Predominantly myopathic scoliosis, joint contractures and hip dysplasia are associated with progressive functional limitation; sensorineural hearing loss and structural ear abnormalities warrant systematic early audiological assessment.

3.1 Frequency of findings

The following tables summarise findings from two dysmorphology sources; occasional discrepancies reflect different underlying series.

Source: [2].

Source: [8] (VSD — ventricular septal defect; ASD — atrial septal defect; CNS — central nervous system).

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4. Clinical Recognition and Warning Signs

Clinical suspicion rests on a combined pattern rather than any isolated sign because no described abnormality is individually pathognomonic [7]. Prenatal ultrasound findings warranting further investigation include early, disproportionate intrauterine growth restriction, polyhydramnios, a single umbilical artery, choroid plexus cysts (particularly bilateral and with other findings), overlapping fetal fingers, abnormal foot positioning and any structural congenital heart disease at the 18-20-week anomaly scan, when syndrome detection sensitivity reaches 90-95% in systematic screening series [3]. More than 90% of affected fetuses have at least one ultrasound abnormality and 55% have two or more [3].

4.1 Prenatal presentations

Prenatal presentation may involve: (1) increased nuchal translucency and/or another suspicious finding, such as omphalocele, at 11–13 weeks; (2) an abnormal maternal serum screening profile in the first or second trimester; (3) an unexpected result from amniocentesis performed for another indication at 16–18 weeks; (4) abnormal fetal ultrasound at 19–22 weeks (intrauterine growth restriction, choroid plexus cysts, congenital heart disease, usually a large ventricular septal defect, renal abnormalities, omphalocele, overlapping fingers or rocker-bottom feet), usually with multiple abnormalities; (5) intrauterine growth restriction often detected only after 32 weeks, polyhydramnios (30–60%) or intrauterine fetal death [5].

4.2 Neonatal recognition

A small-for-gestational-age, hypertonic newborn with characteristic clenched hands, prominent occiput, low-set ears and a cardiac murmur should prompt urgent genetic assessment and karyotyping, even without a prenatal diagnosis. The most striking neonatal findings are low weight for gestational age, short sternum, congenital heart disease and hand and foot abnormalities [5]. Persistent marked feeding difficulty with central apnoea in a dysmorphic newborn reinforces suspicion and warrants expedited chromosomal investigation because early diagnosis directly informs subsequent cardiovascular, renal and neurological assessment. Markedly reduced birth weight helps guide evaluation of radial ray defects, where trisomy 18 should be excluded prenatally or neonatally [28].

Key history elements are pregnancy history and pedigree, which may be brief when a +18 karyotype is already known; key examination elements are growth parameters, dysmorphic features (prominent occiput, simple ears, overlapping fingers, short sternum, short hallux and rocker-bottom feet) and cardiac examination [5]. Clinical photographs of newborns and an older child with trisomy 18, showing clenched hands, crossed legs, narrow pelvis, hypoplastic supraorbital ridges, prominent occiput, low-set malformed ears, index finger overlapping the third, short dorsiflexed hallux and prominent calcaneus, appear in Smith's atlas [8].

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5. Diagnosis: Criteria, Tests and Algorithms

Definitive trisomy 18 diagnosis is always cytogenetic or molecular; clinical criteria alone cannot confirm it without chromosomal testing.

Prenatal screening. Contemporary screening predominantly uses cell-free fetal DNA in maternal plasma (cfDNA, also termed NIPT — non-invasive prenatal testing), recommended by the American College of Obstetricians and Gynecologists (ACOG), American College of Medical Genetics and Genomics (ACMG) and Society for Maternal-Fetal Medicine as the most sensitive and specific screening method for common trisomies, to be available to all pregnant women regardless of maternal age or baseline risk [29,30]. Taylor-Phillips and colleagues' reference meta-analysis estimated pooled sensitivity of approximately 97.4% and specificity near 99.9% for cfDNA trisomy 18 detection [12], supported by subsequent clinical validation, including Norton and colleagues' multicentre trial in the New England Journal of Medicine [13]. Despite this accuracy, cfDNA remains screening rather than diagnosis: a positive result, particularly in low-baseline-risk populations where positive predictive value is substantially lower than in high-risk populations, requires invasive confirmation before definitive clinical or reproductive decisions [29,30]. Second-trimester anomaly ultrasound remains essential for detecting suggestive markers and characterising structural abnormalities unassessed by cfDNA, particularly neural tube and abdominal wall defects.

Combined and biochemical screening. First-trimester trisomy 13 and 18 risk algorithms combine nuchal translucency with maternal serum free beta-hCG (human chorionic gonadotrophin) and PAPP-A (pregnancy-associated plasma protein A) [5]. In second-trimester serum screening, now less used, medians in affected pregnancies are all reduced: alpha-fetoprotein 0.43 MoM (multiples of the median), unconjugated oestriol 0.43 MoM and hCG 0.36 MoM [5]. Combining first-trimester screening, NIPT, second-trimester screening and detailed anomaly ultrasound at 19–20 weeks detects more than 80% of affected pregnancies [5]; combined screening sensitivity is at least 78% [3]. Nuchal translucency, biophysical profile, first-trimester biochemical profile and anomaly ultrasound are screening investigations; karyotyping of placental material, amniotic fluid or umbilical cord blood, fluorescence in situ hybridisation (FISH), NIPT and array-CGH (microarray comparative genomic hybridisation) are the cytogenetic and molecular investigations used [2].

Diagnostic confirmation. Definitive prenatal confirmation through amniocentesis or chorionic villus sampling, or postnatal confirmation through peripheral blood sampling, uses conventional karyotyping, identifying trisomy and distinguishing free trisomy, mosaicism and translocation, with important prognostic and counselling implications. Peripheral blood G-banded karyotyping is the postnatal gold standard [2]. Chromosomal microarray (CMA) is a valid alternative or supplement with higher resolution for segment deletions/duplications, although it cannot independently identify parental balanced rearrangements. FISH or QF-PCR (quantitative fluorescent polymerase chain reaction) allow rapid exclusion of trisomy 18 and triploidy prenatally or neonatally [28]. Parental chromosomal testing is not indicated with simple free trisomy 18 [5].

Systematic postnatal assessment. After confirmation, recommended initial assessment includes echocardiography because of frequent structural heart disease, renal and abdominal ultrasound, transfontanelle ultrasound and/or magnetic resonance imaging, audiological assessment, paediatric ophthalmological assessment and full blood count with differential, following Kepple, Fishler and Peeples' guidelines [9], subsequently incorporated in the 2025 American Academy of Pediatrics clinical report [24]. Chest radiography for rib irregularity and clinical photographic documentation complete investigation [5].

5.1 Test limitations and report content

Each test answers a different question, and its limitations should appear in the report and counselling. Cell-free DNA in maternal plasma is mainly placental (cytotrophoblast), so results reflect the placenta rather than necessarily the fetus: confined placental mosaicism may produce false positives or, conversely, false negatives. In a case published in 2026, three consecutive cell-free DNA tests gave low-risk results despite amniocentesis-confirmed fetal trisomy 18, increased nuchal translucency, hydrops and tricuspid regurgitation; placental analysis showed mosaicism with up to 76% trisomic cells on the fetal side and 20% on the maternal side, reducing "effective fetal fraction" below the test detection threshold (approximately 4%) [31]. A low-risk result therefore does not exclude trisomy 18 with ultrasound abnormalities, and invasive diagnosis decisions depend on ultrasound findings rather than screening alone [30,31].

G-banded karyotyping detects free trisomy and distinguishes translocation and mosaicism, and is the only listed method identifying parental balanced rearrangements; however, resolution is several million base pairs, and mosaicism detection depends on counted cells: the usual 20 metaphases exclude mosaicism of 14% or more with 95% confidence, but not lower levels [32]. With suspected mosaicism and a normal blood karyotype, counting more cells or examining a second tissue (fibroblasts or buccal mucosal cells) increases sensitivity; one tissue's proportion does not predict other tissues' proportions [3,4]. QF-PCR and interphase FISH provide rapid answers limited to tested chromosomes. Chromosomal microarray detects partial gains at higher resolution and defines triplicated regions in partial trisomies but misses balanced rearrangements and may miss low-level mosaicism.

The cytogenetic report should specify tissue, counted cell number and the current international nomenclature formula (ISCN 2024), for example 47,XX,+18 in free trisomy or mos 47,XY,+18[n]/46,XY[n] in mosaicism, with cell numbers for each line in square brackets [33]; microarray formulas should specify genome assembly, such as GRCh38, and gained segment coordinates. Partial trisomies and smaller copy number variants follow joint ACMG and ClinGen (Clinical Genome Resource) constitutional copy number variant standards, with five classes (pathogenic, likely pathogenic, uncertain significance, likely benign and benign) [34]. HGVS (Human Genome Variation Society) nomenclature and MANE (Matched Annotation from NCBI and EMBL-EBI) reference transcripts do not apply to whole-chromosome aneuploidy; they apply, with transcript and version reported, only to monogenic differential diagnosis investigations, such as CHD7 in CHARGE syndrome or NIPBL in Cornelia de Lange syndrome. An uncertain copy number variant does not become pathogenic through a compatible phenotype or partial familial segregation: parental testing investigates origin (de novo or inherited), and reclassification requires formal criteria [34].

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6. Differential Diagnosis

The differential diagnosis should first consider trisomy 13 (Patau syndrome), sharing growth restriction, congenital heart disease, central nervous system abnormalities and generally poor prognosis, but distinguished by more frequent holoprosencephaly, postaxial polydactyly and facial midline defects (bilateral cleft lip/palate and cyclopia in the most severe forms), less typical of trisomy 18. Triploidy (69 chromosomes) may resemble aspects of the phenotype but typically involves partial molar placentomegaly and marked growth asymmetry, readily distinguished by karyotyping. Other clinical differentials include Pena–Shokeir syndrome (fetal akinesia sequence with joint contractures and pulmonary hypoplasia but normal karyotype), CHARGE syndrome (coloboma, heart disease, choanal atresia, growth retardation, genital and ear anomalies associated with pathogenic CHD7 variants), and other syndromic intrauterine growth restriction conditions with cardiac and renal malformations. Definitive distinction ultimately requires chromosomal investigation, underlining karyotyping or microarray's central role in the diagnostic algorithm.

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7. Treatments and Risk Management Strategies

Trisomy 18 is a chromosomal aneuploidy, not a monogenic disorder with a molecular target amenable to pharmacological or gene-based correction. To date, no drug has been approved by regulatory agencies (FDA, EMA or INFARMED) with a specific indication to correct the pathophysiological mechanism underlying trisomy 18, and no pivotal trials of targeted therapy are under way for this condition. Clinical management is therefore predominantly symptomatic and supportive and, when indicated and desired by the family, surgical or interventional — not pharmacological therapy directed at the cause.

Shared decision-making and care planning. The 2025 American Academy of Pediatrics clinical report establishes that intervention intensity, from exclusively palliative comfort care to full surgical intervention, should follow shared decision-making between clinicians and family, informed by family values and goals rather than automatically or categorically determined by chromosomal diagnosis [24]. This differs from earlier decades when most families were offered only palliation without discussion of active alternatives [9,24]. Historical reference texts express that position: Smith's atlas states that limiting extraordinary life-prolonging measures should be seriously considered after diagnosis, taking parental feelings and each child's circumstances into account [8]; a Brazilian manual states that treatment depends on comorbidities, complex assistive technologies and invasive procedures are avoided because of poor prognosis, and palliative care is indicated [2]. Survival is longer in intensively treated infants [5].

Cardiac assessment and management. In patients with haemodynamically significant structural heart disease whose families choose active intervention, surgical repair, most commonly ventricular septal defect closure, has been associated in recent observational series, including Society of Thoracic Surgeons congenital cardiac surgery database analyses, with postoperative and medium-term survival substantially above historical medically managed cohorts, although larger prospective studies of long-term quality of life are still needed [24]. Among 1,020 infants with trisomy 18 (91% with congenital heart disease), cardiac surgery occurred in 7% and was associated with 64% lower hospital mortality, persisting over 24 months [23]. Cereda and Carey's review reported 82–91% survival after palliative and corrective cardiac surgery, and a Japanese series reported median postoperative survival of 179 days [3]. Surgical decisions should consider lesion complexity, major comorbidities, particularly respiratory and neurological, and family care goals.

Other surgical interventions. In the Ontario cohort, 13.8% underwent surgery, ranging from myringotomy to complex cardiac repair, with one-year survival after the first operation of 68.6% [22]. In Baty's series, 13% of survivors underwent neonatal surgery [8].

Respiratory support. Depending on severity and agreed care decisions, apnoea and respiratory failure management includes non-invasive or invasive ventilation, with particular postoperative monitoring because any surgery increases respiratory depression risk.

Nutritional support. Almost universal feeding difficulty means most patients eventually require nasogastric feeding or gastrostomy for prolonged support. Nasogastric feeding is usually initially necessary, with possible gastrostomy in survivors beyond 6 months; gastro-oesophageal reflux prophylaxis should be considered because of its high frequency [5]. Videofluoroscopic swallowing assessment is indicated whenever a substantial proportion of nutrition is oral, to identify overt or silent aspiration.

Prevention of respiratory infection. Given the increased risk of severe respiratory morbidity associated with respiratory syncytial virus (RSV) infection in this group of patients — many of whom have haemodynamically significant congenital heart disease and/or chronic lung disease — prophylaxis with palivizumab (brand name Synagis®) should be considered: a humanised anti-RSV monoclonal antibody given intramuscularly at a dose of 15 mg/kg once a month during the seasonal period of viral circulation, in children younger than 2 years (the European SmPC does not set a maximum number of doses per season, but most of the experience, including the phase III trials, corresponds to 5 injections; after surgery with cardiopulmonary bypass, an additional dose of 15 mg/kg as soon as the child is stable), following the eligibility criteria established by the American Academy of Pediatrics for infants with haemodynamically significant congenital heart disease [35]. The most frequently described adverse effects are local injection-site reactions, fever and, rarely, hypersensitivity reactions; there is no evidence of an increase in serious adverse events specific to the trisomy 18 population. Update: palivizumab is no longer the first-choice prophylaxis and is reserved for situations without access to the current alternatives (it remains registered with the FDA as a prescription medicine, according to Drugs@FDA accessed in October 2026), having been replaced in clinical practice by the long-acting monoclonal antibodies nirsevimab (Beyfortus®, FDA approved in 2023) and clesrovimab (Enflonsia®, FDA approved in 2025), given as a single intramuscular dose per season; nirsevimab is given at a dose of 50 mg in infants weighing less than 5 kg and 100 mg in the others, in the first season, and at a dose of 200 mg (two 100 mg injections) in the second season in children who remain at high risk (up to 24 months under the FDA label; from 8 to 19 months under the AAP), which includes haemodynamically significant congenital heart disease, whereas clesrovimab is not recommended from 8 months of age [36,37]. The US and European labels of nirsevimab and clesrovimab also recommend an additional dose as soon as the child is stable after cardiac surgery with cardiopulmonary bypass, a frequent situation in infants with trisomy 18 who undergo surgery [38–40]. In Portugal, nirsevimab was administered through a seasonal programme in the 2024–2025 season; in a test-negative case–control study from the VigiRSV surveillance network (341 children younger than 24 months, 91.2% without known chronic disease), the adjusted effectiveness against RSV-associated hospitalisation was 78.5% (95% CI: 59.3–89.0%) [41]; this study did not include a relevant number of children with heart disease or chromosomal abnormalities, so its application to this group is an extrapolation. In Brazil, access to these antibodies depends on decisions by the Ministry of Health and CONITEC (Comissão Nacional de Incorporação de Tecnologias no SUS), and regulatory approval does not equate to incorporation into the SUS.

Immunisations. Baty's natural history series showed no increased vaccine adverse reactions [8].

Seizure management. Seizures should follow general paediatric epilepsy principles, with antiseizure medication individually selected by seizure type, comorbidities, particularly cardiac drug interactions and QT prolongation risk with some agents, and response. Comparative drug efficacy literature in this population is limited to small series, so no trisomy 18-specific validated dosing regimen exists; this evidence gap should be explicitly acknowledged rather than filled by unsupported extrapolation.

Oncological surveillance. Because of increased hepatoblastoma risk, international consensus guidance for embryonal tumour predisposition syndromes recommends complete abdominal ultrasound and serum alpha-fetoprotein every three months from birth to age four [26]. A baseline alpha-fetoprotein should be established as early as possible, recognising physiologically high neonatal values that should decline over the first six months; an increase exceeding 50-100 ng/mL relative to the expected trajectory should prompt repeat testing in six weeks and ultrasound reassessment, reserving MRI for sustained elevations [26]. Wilms tumour screening is less consensual, but centres recommending it propose renal ultrasound every three to six months from age one.

Multisystem screening and surveillance. The following table consolidates Kepple, Fishler and Peeples' surveillance protocol, widely adopted in contemporary practice [9]:

(ECMO — extracorporeal membrane oxygenation.)

7.1 Nature of the evidence and principal studies

No randomised trisomy 18 intervention trials exist, and ClinicalTrials.gov lists no therapeutic trials for the condition; registered studies concern prenatal screening, decision tools and palliative care. Active-intervention evidence is observational, requiring distinctions between levels: the 2025 American Academy of Pediatrics report is scientific-society guidance based on literature review and ethical principles [24]; the 2023 American Association for Thoracic Surgery consensus derives from an expert Delphi process [42]; meta-analyses pool retrospective cohorts with moderate bias risk and very low certainty [43,44]; case reports document possibilities rather than frequencies [45]. None is a regulatory authorisation, and US recommendations do not bind Portuguese or Brazilian healthcare systems.

These results do not allow direct strategy comparisons. Operated patients were selected through survival until surgery, higher weight, fewer comorbidities and families and centres choosing intervention; lower mortality associations therefore include selection and immortal time bias, and meta-analysis odds ratios with very wide confidence intervals are not causal effects [43]. The intensive-versus-comfort-care meta-analysis found no survival difference, with only 211 patients and high heterogeneity, which also does not establish absence of effect [44]. Relative hospital mortality reduction does not describe absolute long-term survival or admission burden, which remains high after surgery [47]. Population cohort survival medians (9 days in Ontario) describe all live births rather than prognosis for an infant surviving the first weeks; ten-year survival differs substantially by cytogenetic status, so pooled complete, mosaic and partial trisomy data should not be transferred to one subtype [46]. All studies lack validated child and family quality-of-life measures.

7.2 Regulatory status of drugs used

No drug has a trisomy 18-specific United States or European Union indication. Drugs used in these children are authorised for general indications (heart disease, epilepsy, reflux or infection), following each label's age, weight and indication; trisomy 18 alone is neither an indication nor a contraindication. RSV prophylaxis exemplifies a label directly addressing haemodynamically significant congenital heart disease.

Antibody efficacy in infants with heart disease was not demonstrated in trisomy 18-specific trials. Palivizumab has a randomised trial in haemodynamically significant congenital heart disease (1,287 children): RSV hospitalisation fell from 9.7% with placebo to 5.3%, a 45% relative reduction (p=0.003), corresponding to a 4.4 percentage-point absolute difference [49,51]. Nirsevimab and clesrovimab efficacy was demonstrated in healthy premature and term infants (nirsevimab: medically attended RSV lower respiratory infection 1.2% versus 5.0% with placebo, efficacy 74.9%, 95% CI: 50.6–87.3%; clesrovimab: 0.026 versus 0.065 cases over 5 months, efficacy 60.5%, 95% CI: 44.2–72.0%) and extrapolated to infants with heart disease from similar pharmacokinetic exposure in palivizumab-comparator trials not powered for efficacy [38,39]. Use in a child with trisomy 18 and heart disease is thus on-label, addressing age and season rather than chromosomal diagnosis, supported by efficacy extrapolation; clesrovimab in a second season or nirsevimab after 24 months would be off-label in both jurisdictions.

The same reasoning applies to other drugs: antiseizure medications, proton pump inhibitors and diuretics have not been studied in trisomy 18, and efficacy is extrapolated from general paediatric populations; off-label status depends on jurisdictional label wording for age and indication rather than trisomy 18 diagnosis.

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8. Reproductive Options and Family Counselling

Genetic counselling following a diagnosis of trisomy 18 should begin by establishing the underlying aetiological mechanism, because this directly determines the recurrence risk. In nonmosaic free trisomy 18 arising from sporadic meiotic nondisjunction, the recurrence risk in future pregnancies is generally estimated at approximately 1%, slightly above the population baseline; this increase is more pronounced in women who were younger at the index trisomic pregnancy than in women already approaching advanced maternal age [3,6]. The sources agree that the recurrence risk in siblings is low, but quote slightly different estimates: 0.55% (1/200) in Baty's series; no recurrence of +18 among 170 cases in a Japanese series; and a relative risk of 3.1 following a previous pregnancy with trisomy 18 (De Souza), higher in women younger than 35 years at the index pregnancy; Cereda and Carey propose 1% for counselling [3,5,8]. In women older than 37 years, the risk of a pregnancy with trisomy 21 exceeds the recurrence risk of trisomy 18 [5]. When a translocation is identified, chromosome analysis of both parents is mandatory: if either carries a balanced translocation, the recurrence risk may be substantially higher and varies with the chromosome involved and the type of translocation. This warrants referral for specialist genetic counselling and discussion of preimplantation genetic testing (PGT) during assisted reproduction, or early prenatal diagnosis in subsequent spontaneous pregnancies. In mosaicism, the recurrence risk is usually considered close to that of the general population, although the literature provides limited data for this particular estimate [4]. The risk to the offspring of individuals with mosaicism is variable: among 12 affected individuals older than 20 years, four had a child with complete trisomy 18, while another three had a total of five healthy children [8].

Prenatal diagnosis in subsequent pregnancies. Invasive prenatal diagnosis by chorionic villus sampling or amniocentesis should be offered; given the low recurrence risk, some couples prefer pregnancy surveillance through first-trimester screening, NIPT, second-trimester serum screening and a detailed fetal anomaly scan at 19–20 weeks [5].

For ongoing pregnancies with prenatally confirmed trisomy 18, counselling should follow the principles of family-centred care, providing balanced, current and nondirective information about the range of possible outcomes—from spontaneous fetal loss, which is extremely common after prenatal diagnosis, to prolonged survival in some cases—available options (including termination of pregnancy where legally permitted and desired by the family, or continuation with advance planning of neonatal care), and support resources. These include family support organisations such as SOFT (Support Organization for Trisomy 18, 13, and Related Disorders), active in the United States with international links to corresponding groups such as SOFT UK (Support Organisation for Trisomy 18/13; http://www.soft.org.uk) in the United Kingdom [5]. In Europe, the relevant European Reference Network is ERN ITHACA (European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability), which brings together clinical genetics and dysmorphology centres and can support discussion of complex cases [14]. The spontaneous fetal loss rate from the second trimester onwards is 36% [5]; according to a Brazilian handbook, only 2.5% of fetuses with trisomy 18 survive to birth, and 30% of those reaching the second trimester are born alive [2].

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9. Special Considerations: Population Diversity and Epidemiology

Trisomy 18 has no documented ethnic or racial predominance. Advanced maternal age is the main known epidemiological determinant, as in other autosomal trisomies caused by meiotic nondisjunction [3,16]. However, a consistent female predominance among live births is estimated at approximately 3:1. Its mechanism remains incompletely understood, although greater intrauterine lethality in affected male fetuses has been proposed. Supporting this hypothesis, the sex ratio in electively terminated pregnancies approaches parity (approximately 48:51) [3].

Birth prevalence varies between population series, ranging from approximately 1:3,600 to 1:10,000 live births, whereas overall prevalence—including spontaneous fetal losses and terminations following prenatal diagnosis—is substantially higher, approaching 1:2,500 conceptions [3]. Other estimates include 0.3 per 1,000 newborns [8], 1:7,900 live births [5], and 1:6,000 to 1:8,000 live births, with recent estimates as low as 1:8,600 to 1:10,000 and overall prevalence of 1:2,500 to 1:2,600 [2,3]. This discrepancy reflects the high rates of spontaneous fetal loss and elective termination following prenatal diagnosis in many healthcare systems, an important confounder when comparing birth prevalence across countries and registration systems.

No robust data currently document a specific population founder effect for trisomy 18, unlike some recessive monogenic diseases in geographically or culturally isolated populations. This is expected because free trisomy is a sporadic, nonhereditary meiotic nondisjunction event and is therefore not subject to the mechanisms of genetic drift and consanguinity that produce founder effects. Regional clinical practice differs in the rates at which cardiac surgery is offered to these patients: Japanese series have reported one- and two-year survival rates higher than those historically described in Europe and North America, associated with earlier and more systematic use of cardiac drug treatment and, in some centres, corrective surgery. These findings illustrate how variation in clinical practice, as well as disease biology, substantially influences reported outcomes [24]. Population registries distinguish total prevalence from live-birth prevalence. In 21 European EUROCAT registries (6.1 million births, 1990–2009), total trisomy 18 prevalence (live births, fetal deaths from 20 weeks onwards and terminations for fetal anomaly) was 5.0 per 10,000 births (95% CI: 4.8–5.1), while live-birth prevalence was 1.04 per 10,000 (95% CI: 0.96–1.12); total prevalence increased with maternal age, while live-birth prevalence remained stable because of prenatal diagnosis [52]. In an analysis of 24 registries from 18 countries in Europe, the Americas and Asia (International Clearinghouse for Birth Defects Surveillance and Research), mean total prevalence in registries including terminations was 4.08 per 10,000 (95% CI: 3.01–5.15), and live-birth prevalence was 1.07 per 10,000 (95% CI: 0.77–1.38), higher where termination was prohibited. This analysis included South American hospital registries—ECLAMC (Estudo Colaborativo Latino-Americano de Malformações Congénitas, 538 trisomy 18 cases between 1995 and 2014), Argentina's RENAC network and Colombian registries—without a separate Brazilian prevalence estimate [53]. These registry figures measure different outcomes and should not be conflated: total prevalence depends on the inclusion of fetal losses and terminations, while live-birth prevalence depends on access to prenatal diagnosis and termination.

Published Brazilian data mainly comprise referral-centre series describing patients seen rather than population prevalence. At a clinical genetics referral service in Porto Alegre, 64 patients with karyotype-confirmed trisomy 18 (1975–2020), most admitted to intensive care, had cleft lip in 4.68% and cleft lip and palate in 3.11% [54]. At a quaternary university hospital in São Paulo (2014–2018), among 27 newborns with trisomy 18 and heart disease admitted to intensive care, in-hospital mortality was 59%; four patients in the combined trisomy 13 or 18 group underwent heart surgery, and palliative care was offered to 54% [55]. At a maternity referral centre for high-risk fetal conditions in Rio de Janeiro participating in ECLAMC (2018–2023), Edwards syndrome was the second most frequent genetic syndrome among newborns with congenital heart disease (29 of 95 syndromic cases), with prenatal diagnosis in 93.3% of heart disease cases [56]. In Portugal, the population-based Registo Nacional de Anomalias Congénitas (RENAC), maintained by the Instituto Nacional de Saúde Doutor Ricardo Jorge, follows EUROCAT standards. Between 1997 and 2016 it documented prenatal diagnosis in 56.1% of registered congenital anomaly cases [57], but the sources consulted did not identify a publication reporting trisomy 18 prevalence specifically in Portugal; this does not mean that the registry lacks such data. The Brazilian handbook Síndromes Genéticas: Reconhecer para Tratar reproduces international estimates (1:6,000 to 1:8,000 live births) and a proportion of 63% of mothers older than 35 years, without its own Brazilian population registry data [2].

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10. Illustrative Clinical Case

10.1 Composite case: prenatal diagnosis and shared decision-making

This composite clinical case is provided solely for teaching purposes and does not describe an identifiable real patient.

A 38-year-old primigravida is referred after the 20-week fetal anomaly scan identifies symmetrical fetal growth restriction, a single umbilical artery, bilateral choroid plexus cysts and findings consistent with a ventricular septal defect. Cell-free fetal DNA screening, previously performed because of advanced maternal age, had reported an increased risk of trisomy 18. Given these concordant findings, amniocentesis is proposed, and the karyotype confirms 47,XX,+18, nonmosaic free trisomy. A multidisciplinary genetic counselling consultation involving a geneticist, neonatologist and maternal–fetal medicine obstetrician provides a balanced discussion of possible outcomes, available reproductive options and, if the family chooses to continue the pregnancy, advance planning of neonatal care, including the possibility of cardiac intervention if desired.

After the family's informed decision to continue the pregnancy with an active care plan, delivery takes place at 37 weeks by elective caesarean section, without major immediate complications. The female newborn weighs 2100g and has axial hypotonia with distal hypertonia, clenched hands with characteristic overlapping fingers, a prominent occiput and low-set ears. Neonatal echocardiography confirms a moderately sized perimembranous ventricular septal defect without significant immediate haemodynamic consequences. Renal ultrasonography is normal, and audiological assessment identifies mild bilateral sensorineural hearing loss. Nasogastric tube feeding is started because videofluoroscopy documents difficulty coordinating sucking and swallowing, with planned reassessment for gastrostomy if the need persists beyond a few weeks.

At four months of age, as heart failure symptoms associated with the septal defect progress, the paediatric cardiology team discusses the risks and potential benefits of surgical correction with the family through an explicit shared decision-making process. Surgery is completed successfully without major perioperative complications, requiring eight days of postoperative mechanical ventilation. Cancer surveillance with quarterly alpha-fetoprotein testing and abdominal ultrasonography is initiated. At eighteen months of follow-up, there is no evidence of an embryonal malignancy; psychomotor development is slow but progressive, the child smiles and interacts with family members, and there have been no further admissions for major respiratory decompensation since surgical discharge.

The case illustrates the gradual shift in contemporary clinical practice towards informed, individualised shared decision-making centred on family values and goals, replacing a deterministic approach limited to palliative care, as advocated in the American Academy of Pediatrics' 2025 clinical report [24].

10.2 Published case: a 16-year-old adolescent with complete trisomy 18

In 2025, Tate, Ward and Snider described a 16-year-old girl with karyotype-confirmed complete trisomy 18, seen at a paediatric follow-up appointment because of worsening epileptic seizures [45]. At birth, her parents had been advised to prepare for her death and decline surgery, but chose intervention: an omphalocele and intestinal malrotation were corrected during the neonatal period, and a gastrostomy was placed, on which she remained dependent. At three months, an atrial septal defect, ventricular septal defect and patent ductus arteriosus were closed. She also had a bicuspid aortic valve, Dandy–Walker malformation, neurogenic bladder with recurrent urinary tract infections, obstructive sleep apnoea and hearing loss. Over her lifetime she underwent appendicectomy, cholecystectomy, renal abscess resection, liver biopsy and bladder stone removal. Seizures began at 9 years and progressed to refractory myoclonic and generalised epilepsy, classified as Lennox–Gastaut syndrome; a vagus nerve stimulator was implanted at 13 years, and several antiseizure medications failed. Development progressed to the point of almost walking unsupported, but at 11 years she experienced an encephalopathic event of undetermined cause, followed by neurological regression and growth arrest. On examination she was nonverbal and entirely dependent, with a prominent occiput, micrognathia, low-set ears, clenched hands, knee flexion contractures, clubfeet and right hip dysplasia; a palliative care team supported the family. On the general Centers for Disease Control and Prevention charts, height and weight were below the 3rd and 1st percentiles, but on trisomy 18-specific charts her progress was as expected until age 11. These charts, showing the patient's measurements, appear as figures 1 and 2 in the original open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC11822554/) [10,45].

This case documents prolonged survival rather than its probability: the patient belongs to the small group who survive beyond 10 years in population cohorts [22,46]. It also shows that early cardiac surgery is compatible with prolonged survival, that noncardiac morbidity (epilepsy, feeding difficulties, urinary and respiratory infections, and orthopaedic problems) dominates adult life, and that syndrome-specific growth charts help avoid misinterpreting an expected growth trajectory as growth failure. The drugs and procedures used in this patient reflect individual decisions by the authors and are not routine recommendations.

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11. Prognosis and Long-Term Follow-Up

Trisomy 18 remains associated with high overall mortality, estimated at 75%–95% in the first year of life in the largest population series, with central apnoea, respiratory failure and complications of congenital heart disease most frequently implicated [9,20]. Seventy per cent of deaths are due to cardiorespiratory arrest, with central apnoea a major factor in the neonatal period and first year [5]. Historically, median survival in cohorts without active intervention was only a few weeks, with just 5%–10% of affected individuals reaching one year of age [10,11]. Published median survival estimates range from 3 to 14.5 days; 60–75% survive 24 hours, 22–44% one month and approximately 50% more than one week [2,3,5,8]. One reference source reports a median life expectancy of 4 days, with a wide range from failure to establish breathing at birth to more than 2 years [5]; another reports that 50% die in the first week and many of the remainder in the following 12 months, with median survival of 14.5 days [8]. More recent studies, reflecting increasing use of supportive and sometimes surgical interventions, have documented higher proportions surviving beyond one year—estimated at 3%–25%, depending on the intensity and number of medical interventions offered—and an increasing number of long-term survivors, including patients reaching their second decade [9,21]. In the Ontario population cohort (254 children with trisomy 18 born between 1991 and 2012), median survival was 9 days, one-year survival 12.6% and ten-year survival 9.8% [22]. In the international analysis of 24 registries, median first-week mortality was 42%, half occurring on the first day, while first-year mortality was 88% in the 16 registries with complete follow-up, with approximately 10% surviving to one year and cumulative five-year survival of approximately 7.7% [53]. In the Texas birth defects registry (503 live births with trisomy 18 between 1999 and 2008), 8.6% survived to age 10; ten-year survival was 6.6% in complete trisomy and 43.8% in mosaic or partial trisomy, and noncomplete cytogenetic status accounted for 27.9% of ten-year survival (population attributable fraction) [46]. These figures apply to all live births in each registry and should not be transferred from one cytogenetic subtype to another. At least 10 reports describe affected children older than 10 years [8], and Baty and colleagues described a patient with +18 aged 19 years [5]. In Baty's series, survivors spent a mean of 16.3 days in neonatal intensive care and 10.1 days receiving mechanical ventilation [8]. Respiratory and cardiovascular complications are the leading causes of mortality, and 100% of cases have severe intellectual disability [2].

Long-term survivors consistently have severe cognitive impairment and marked motor delay. Independent walking is rare even among those surviving beyond early childhood, and verbal communication is usually limited to a small number of words. The developmental quotient (developmental age/chronological age) averages 0.18, indicating severe to profound delay, and decreases in older children [5]. Nevertheless, these children continue to make progress over time: their divergence from typical developmental milestones reflects a substantially slower rate of acquisition rather than loss of acquired skills. Many can recognise relatives and carers, express preferences and engage emotionally with those around them. These abilities should be communicated in family counselling to avoid a perspective focused exclusively on impairment. Some older children smile, laugh and engage with their families, and all achieve some psychomotor maturation and continue learning [8]; reported abilities include understanding words and sentences, using a walking frame, feeding independently and following simple instructions [3].

Long-term follow-up should maintain the systematic multisystem surveillance described in Section 7, particularly growth monitoring using trisomy 18-specific charts rather than general population charts, periodic cardiological reassessment, orthopaedic surveillance for scoliosis from two years of age, and continued occupational therapy, physiotherapy and speech and language therapy, started as early as possible and tailored to each patient's needs. Trisomy 18-specific length, weight and head circumference charts were published by Baty and colleagues [8,10].

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12. Summary and Final Considerations

Trisomy 18 is a multisystem autosomal aneuploidy whose natural history is characterised by high early mortality. However, the range of outcomes has proved more heterogeneous than historically recognised as more centres adopt shared decision-making and, in some cases, active supportive interventions and corrective surgery. Diagnosis now draws on highly sensitive and specific prenatal cell-free fetal DNA screening, always confirmed by definitive chromosome analysis. In the absence of treatment targeting the underlying chromosomal mechanism, clinical management depends on systematic, coordinated surveillance of the multiple affected systems—cardiovascular, respiratory, neurological, renal, oncological, auditory, ophthalmological, orthopaedic and nutritional—and an ongoing shared decision-making process with the family, informed by current evidence rather than automatically determined by the genetic diagnosis. Recent international guidance, culminating in the American Academy of Pediatrics' 2025 clinical report, reflects growing recognition that these children and their families are entitled to individualised, compassionate, scientifically grounded care throughout their clinical course, regardless of its duration.

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