Heteropagus Twinning and Conjoined Twins

Anomalies of monochorionic twinning: symmetrical conjoined twins, heteropagus (parasitic) twins, twin reversed arterial perfusion sequence (TRAP, acardiac twin) and fetus in fetu; non-hereditary conditions, with a recurrence risk described as negligible.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Scope and definitions

Monozygotic twinning, in which a single oocyte fertilised by a single spermatozoon gives rise to two individuals, occurs in about 1 in 200 births and is considered the most frequent aberration of morphogenesis in the human species [2]. Within this category, monochorionic pregnancies, which share a single placenta, concentrate a set of complications that do not exist in dichorionic pregnancies: twin-to-twin transfusion syndrome, twin anaemia-polycythaemia sequence (TAPS), twin reversed arterial perfusion sequence (TRAP), monoamniotic pregnancy and conjoined twinning [12]. This article covers the class of anomalies of monochorionic twinning in which one of the twins is structurally incomplete or joined to the other: symmetrical conjoined twins, heteropagus (parasitic) twins, acardiac twin (TRAP sequence) and fetus in fetu, the latter as a borderline entity and differential diagnosis.

Conjoined twins are two monozygotic individuals joined at an anatomical region, with variable sharing of organs; their placentation is always monochorionic and monoamniotic [7, 12]. Heteropagus twins are asymmetrical conjoined twins in which the tissues of a severely defective twin, the parasite, depend on the cardiovascular system of the other, the autosite, which remains largely intact [4]. The TRAP sequence is defined by the complete or partial absence of cardiac development in one twin, the acardiac twin, whose circulation is entirely sustained by the morphologically normal co-twin, the «pump» twin, through a placental arterio-arterial anastomosis [5]. Fetus in fetu is a fetiform mass, with a vertebral column, encapsulated within the body of a normal twin, most often in the retroperitoneum [15]. Rowena Spencer, drawing on more than 1260 published cases, proposed that these forms constitute a continuum of abnormal conjoined twinning: depending on the site of union and the extent of damage to one of the embryos, the result is an external parasite, an enclosed fetus in fetu, an internal teratoma or an acardiac twin connected through the placenta [23].

1.2. Historical overview

Depictions of joined twins are very ancient and appear in pre-Columbian pottery of the Moche culture, in Peru, and in other cultures [7, 24]. The oldest documented European cases include the «Biddenden Maids», Mary and Eliza Chulkhurst, pygopagus twins born in 1100 in Kent, England, and a pair of rachipagus twins born in Isle-Brewers [7]. The Hungarian sisters Helena and Judith (1701–1723) and the sisters Rosa and Josepha Blazek (1879–1922), from Bohemia, were also pygopagus; Rosa reportedly gave birth to a son in 1910, the only known example of a conjoined woman who had a healthy child [7]. Ambroise Paré (1510–1590) already described the types of union used in the current classification and the first observation of an acephalic and acardiac body attached to the abdomen of another individual, that is, of a heteropagus twin [3, 7]. The first description of an acardiac twin is attributed to Benedetti, in 1533 [8].

The expression «Siamese twins» derives from Chang and Eng Bunker, born in Siam (now Thailand) in 1811 and who died in North Carolina in 1874; they were joined at the lower chest and epigastrium by soft tissue and shared the liver, married two sisters, had 21 children and lived 63 years without separation [7, 25]. The anatomical description of the two brothers varies between sources: the ICBDSR study classifies them as xiphopagus (thoracopagus) and the review by Boer and colleagues as omphalopagus [7, 24]. Between the Middle Ages and the nineteenth century, conjoined twins were exhibited in circuses and fairs, and academic interest focused on the descriptive European teratology of the eighteenth to twentieth centuries [24, 26].

1.3. Scientific milestones

At the experimental level, Stockard showed in 1921, in the fish Fundulus, that changes in temperature and oxygen could simultaneously induce monozygotic twinning and early malformations such as cyclopia, which supported the idea of a common cause for twinning and early malformations [2]. Kurt Benirschke, a placental pathologist, showed that the vast majority of monochorionic placentas have vascular anastomoses and described, with Harper in 1977, the acardiac anomaly as a consequence of an arterio-arterial anastomosis with flow reversal [2]. Schinzel and colleagues (1979) showed that the malformations of monozygotic twins are predominantly early defects [2]. Lehr and Dire reported the first prenatal diagnosis of an acardiac twin in 1978 [8]. The first successful separation of craniopagus twins dates from 1952 [27]. In 2011, the ICBDSR published the largest epidemiological series of conjoined twins, with 383 pairs [7], and in 2025 the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) updated its recommendations for twin pregnancy, including the management of TRAP, monoamniotic pregnancy and conjoined twins [12].

1.4. Nomenclature

The nomenclature of conjoined twins uses the most prominent site of union followed by the Greek suffix «-pagus», meaning «fixed» [25]. Spencer grouped symmetrical conjoined twins into four major groups — ventral, lateral, caudal and dorsal union — with eleven entities [24]. Some authors do not accept combined types such as cephalothoracopagus or thoraco-omphalopagus, considering that cephalopagus almost always includes part of the thorax and thoracopagus part of the abdomen [7]. In the TRAP sequence, the classic terminology describes the acardiac twin as acephalus, anceps, acormus or amorphus [8]. Heteropagus twins are named after the site of union used for symmetrical conjoined twins, with the qualifier «parasitic» [3].

2. Molecular Genetics and Pathophysiology

2.1. Absence of associated genes and genetic position of the class

None of the entities in this article has an associated gene. In the ICBDSR study, which brought together 383 pairs of conjoined twins, there were no familial cases, consanguinity was reported in 5 of 209 cases (2.38%; 95% CI 0.78–5.49) and all karyotypes performed, in 12.1% of pairs, were normal; no association with genetic, demographic or environmental factors was identified [7]. Among about 1500 descendants of Chang and Eng Bunker several pairs of twins were born, including monozygotic twins, but no conjoined pair, according to the review by Mutchinick and colleagues [7]. Online Mendelian Inheritance in Man (OMIM) has no phenotype entry for conjoined, heteropagus or TRAP twins; the closest entry, MIM 276410, describes monozygotic twinning, with no associated gene [11]. That entry brings together the description by Harvey and colleagues (1977) of 10 families with several pairs of monozygotic twins, transmitted through both fathers and mothers, the pedigree of Shapiro and colleagues (1978) with 4 pairs of monozygotic twins, interpreted as autosomal dominant inheritance in a subgroup, and the increase in zygotic splitting after ovulation induction described by Derom and colleagues (1987), considered the first biological mechanism identified as influencing the rate of monozygotic twinning [11]. Smith likewise reports monogenic dominant inheritance in isolated families and the experimental induction of monozygotic twinning by delayed fertilisation of the oocyte in the rabbit and by vincristine in the rat [2]. Boer and colleagues cite a four-generation pedigree with monozygotic female twins and X-chromosome variants described by Liu in 2018, as an indication that monozygotic twinning may have genetic components not yet defined [24].

Prenatal exposure to griseofulvin was suggested in two pairs of conjoined twins in 1987, but this was not confirmed: in a Hungarian population-based study with 22,843 cases with malformations and 38,151 controls, none of the 55 mothers of conjoined twins had taken griseofulvin [7]. An apparent cluster of 5 pairs in 96,438 births in the Rivne region, near Chernobyl, between 2000 and 2006, was interpreted by the ICBDSR authors as too small for conclusions [7].

2.2. Timing of splitting and placentation

The placentation of monozygotic twins depends on when the embryo splits. Sources differ in the figures: the Oxford Desk Reference states that splitting up to day 3 gives rise to dichorionic diamniotic placentation (25% of monozygotic pregnancies reaching term), between days 4 and 8 to monochorionic diamniotic (70–75%), between days 9 and 12 to monochorionic monoamniotic (1–2%) and between days 13 and 14 to conjoined twins, which are rare and 75% female [14]. Smith's Recognizable Patterns of Human Malformation places the formation of two embryonic centres in the blastocyst at 4–5 days, at the origin of monochorionic diamniotic placentation, and the final limit of splitting at 15–16 days, with more than one Hensen's node and primitive streak, at the origin of monochorionic monoamniotic placentation, which accounts for about 4% of monozygotic twins [2]. Boer and colleagues give proportions of 18–36% dichorionic diamniotic, 60–80% monochorionic diamniotic and 1–4% monochorionic monoamniotic [24]. The differences reflect different methodologies and populations and do not alter the central idea: conjoined twins belong to the late end of the spectrum, at the primitive streak stage (Carnegie stage 6, days 12–15, according to the ICBDSR; days 15–17 according to Smith) [2, 7].

Sources: [14, 24]. Smith places monochorionic monoamniotic placentation at about 4% of monozygotic twins and the origin of conjoined twins at the primitive streak stage [2].

2.3. Theories on the origin of conjoined twins

Two theories compete to explain them. The fission theory, more widespread in textbooks, proposes that conjoined twins result from incomplete division of the embryonic axis of a single embryo at around days 15–17; Kaufman maintained that, with the exception of parasites, «the same parts are always joined to the same parts» and that, if fusion explained all conjoined twins, mirror imaging would be equally frequent in joined and separate monoamniotic twins [7, 24]. The secondary fusion theory, advocated by Spencer, proposes that two initially separate embryos come into contact and fuse homologously; in her «spherical theory», two embryonic discs floating on a common yolk sac would produce ventral, lateral or caudal unions, and two discs on a common amniotic cavity would produce dorsal unions by fusion of the neural folds [24]. Spencer stated that no theoretical fission, in any plane, explains the selection of the observed sites of union [7].

Boer, Schepens-Franke and Oostra (2019) propose a third hypothesis: the initial duplication of morphogenetic axial primordia (primitive streak, node, pit) on a single embryonic disc, in which the distance and angle between the two primordia determine the site and degree of union [24]. In favour of this hypothesis they invoke animal experimentation, in which axis duplication was induced by injection of Wnt, β-catenin, plakoglobin, Nodal or noggin RNA, by Activin or Vg1 grafts, and in Cerl−/−;Lefty1−/− or Tcf3−/− mutant mice with ectopic primitive streaks or nodes [24]. The authors accept fission as a plausible mechanism for dichorionic and monochorionic diamniotic twins and secondary fusion as a probable mechanism for dorsal conjoined twins (craniopagus, pygopagus and rachipagus), which have two umbilical cords, individual internal organs and sometimes non-homologous unions, but reject both as an explanation for ventral, lateral and caudal conjoined twins [24]. They also note that they found no descriptions of monochorionic monoamniotic twins after medically assisted reproduction, unlike what happens with dichorionic and monochorionic diamniotic twins [24].

2.4. Embryological adjustments: neoaxial orientation and interaction aplasia

Two mechanisms, exclusive to non-dorsal conjoined twins, explain the morphology of the zones of union. In neoaxial orientation, when the two primordia are in opposite positions, the homologous structures of each embryo divide in the median plane and the halves deviate laterally, forming composite structures with an equal contribution from both twins and rotated 90° relative to the original position; the extreme example is cephalothoracoileopagus, with two composite faces on opposite sides of a single head [24]. In interaction aplasia, when the primordia are parallel or angled, the structures of the contact zone do not form, in proportion to the proximity and the angle; the mechanism is attributed to conflicting morphogen gradients and is typical of parapagus [24]. These mechanisms explain the continuous variation between types and the statement that no two pairs of conjoined twins are alike; for example, cephalothoracoileopagus twins with deviated axes may have a hypoplastic face that mimics holoprosencephaly [24].

2.5. Laterality and early malformations

In dicephalus, the right-sided twin almost always has situs inversus, and anencephaly is frequent, usually in one head only [2]. Monozygotic twins in general have an excess of early malformations — sacrococcygeal teratoma, sirenomelia sequence, VACTERL association, cloacal exstrophy, holoprosencephaly and anencephaly —, concordant in only 5–20% of pairs; when one twin has the severe form, the other may have a lesser degree of the same defect [2]. The interpretation of Stockard and of Schinzel is that the same disturbance that produces twinning produces the early malformation [2]. A complementary hypothesis is that, in the initial phase, the cytoplasm of a single oocyte sustains two embryos before implantation [14].

2.6. Placental anastomoses and pathophysiology of the TRAP sequence

Almost all monochorionic placentas have vascular anastomoses connecting the two fetal circulations, randomly distributed and visible on the fetal surface; vessel calibre reflects the flow carried, and the architecture of these anastomoses determines the risk profile [2, 12]. Smith organises the structural defects of monozygotic twins into four origins: the same factor that caused the twinning (early malformations), incomplete twinning (conjoined twins), placental vascular anastomoses (disruptions, including acardiac and amorphous twins, and twin-to-twin transfusion) and intrauterine constraint (deformations, not increased in monozygotic compared with dizygotic twins) [2].

Source: [2].

In the TRAP sequence, a large-calibre arterio-arterial anastomosis, usually accompanied by a veno-venous anastomosis and close cord insertion, allows the arterial pressure of one twin to overcome that of the other at an early stage of morphogenesis [2, 12]. The «overpowered» twin then receives arterial blood already deoxygenated by the co-twin, which enters through the iliac arteries and preferentially perfuses the lower half of the body; the result is a combination of disruption of already formed tissues and malformation of tissues being formed, with variable absence of the head, heart, upper limbs, lungs, pancreas and proximal bowel [2]. There is a continuous gradation between the amorphous twin, the acardiac twin and lesser forms of disruption [2]. Two pathogenic pathways have been proposed: an early aberrant placental vascular pattern with flow reversal, or a primary defect of cardiogenesis (chromosomal or environmental) with secondary perfusion through the anastomoses [8]. Spencer regards the almost constant absence of a functioning heart and of a competent brain in parasites, fetus in fetu and acardiac twins as an argument for a primary cardiac malformation with secondary cerebral disruption [23]. Van Gemert and colleagues estimate that, taking into account early cessation of development of the acardiac twin in 58% of cases, the sequence occurs in about 1 in 8 monochorionic placentas with arterio-arterial and veno-venous anastomoses [13].

The pump twin sustains two circulations. The consequences described are cardiac overload with cardiomegaly and decompensation, secondary hepatic dysfunction, hypoalbuminaemia, oedema and hydrops; polyhydramnios and uterine overdistension, which favour premature rupture of membranes and preterm birth; and hypoxia with growth restriction, owing to the return of deoxygenated blood [2, 5, 8].

2.7. Heteropagus twins: pathogenesis and zygosity

The most widely accepted theory for heteropagus twins, proposed by Dönitz, is that of a vascular compromise that makes the parasite's tissues dependent on collaterals from the autosite, with selective ischaemic atrophy of the parts deprived of blood supply [3]. Spencer interprets parasites as conjoined twins in which one of the embryos died or deteriorated, the site of insertion indicating the original point of union; the frequent identification, during surgery, of vascular pedicles derived from the autosite and of hypoplastic cords supports this interpretation [3]. In Spencer's review, the blood supply of the parasite came, in omphalopagus and thoracopagus, from somatic vessels (subclavian, internal mammary, intercostal) and, in ischiopagus, from the median sacral artery or the iliac arteries [3]. Monozygosity was confirmed by DNA analysis in some cases, but Logroño and colleagues described a newborn with the lower half of a male parasite joined perpendicularly to the thorax, in which DNA typing demonstrated dizygosity, and proposed fusion of two embryos followed by resorption of the cranial half of one of them [28]. Mathur and colleagues consider this hypothesis hardly generalisable, because other perpendicular parasites were monozygotic and no other cases of dizygosity have been published; Boer and colleagues note that genetic divergence between members of a pair does not imply dizygosity, given the occurrence of post-zygotic mutations, mosaicism, epigenetic changes and skewed X inactivation in monozygotic twins [3, 24].

In fetus in fetu, the karyotype of the host and the mass was identical in 8 cases and protein polymorphisms in 4; in one case studied with 7 polymerase chain reaction (PCR) markers on 4 chromosomes, the alleles were identical and heterozygous at all loci, which supports a monozygotic twin origin [9]. In a newborn treated in Lisbon, a marker informative for uniparental isodisomy of chromosomes 14 and 15 also showed no genetic difference between the host and the mass [10].

2.8. Genetic discordance between monozygotic twins

Monozygotic twins are not genetically identical in the strict sense: discordance may result from de novo dominant mutation, aneuploidy, copy-number variation, differential X-chromosome inactivation, loss or gain of imprinting, mitotic recombination and differing mitochondrial load [14]. Documented examples are two monochorionic diamniotic female twins with severe and mild haemophilia A due to skewed X inactivation, and monozygotic twins discordant for Beckwith-Wiedemann syndrome due to an imprinting alteration at KCNQ1OT1 [14]. The OMIM entry for monozygotic twinning adds the epigenetic differences (DNA methylation and histone acetylation) that accumulate over life, described by Fraga and colleagues in 2005 [11]. These mechanisms have consequences for prenatal diagnosis, because monozygotic twins may be discordant for chromosomal anomalies, mosaicism, imprinting defects and new dominant mutations [14].

3. Clinical Spectrum and Manifestations by System

3.1. Classification of symmetrical conjoined twins

The classification used by the ICBDSR recognises eight well-defined symmetrical types, a category of rare types and a category of asymmetrical conjoined twins, which includes parasites and fetus in fetu [7]. Spencer's classification, taken up by Boer and colleagues and by the São Paulo group, organises symmetrical twins into ventral, lateral, caudal and dorsal unions [24, 25]. The most useful distinction in practice is between non-dorsal conjoined twins, which always have a single umbilicus and cord (sometimes with a common omphalocele) and show neoaxial orientation or interaction aplasia, and dorsal conjoined twins, which have two umbilical cords and individual internal organs [24].

Source: classification and proportions [7].

Ventral conjoined twins form a continuum. Xipho-omphalopagus, the mildest form, has joined livers and a common peritoneal cavity and is a good candidate for separation; omphalopagus twins share liver and diaphragm, may have pericardial and cardiac displacements without cardiac union and share bowel in about one third of cases; thoracoileopagus twins have a single composite heart and are almost never separable; prosopothoracoileopagus and cephalothoracoileopagus, joined from the face or head to the umbilicus, are non-viable [24]. Parapagus twins share extensive parts of the body, separation is generally impossible and most die in the perinatal period [24]. Ileoischiopagus, a caudal type, shares the lower abdomen, pelvis and perineum, and usually has two hearts and four upper and lower limbs (or three lower limbs, in the tripus form) [24, 25].

Among dorsal types, craniopagus twins are joined at the vault (frontal, temporal, parietal, occipital or non-homologous combinations), may share the superior sagittal sinus and other dural sinuses and, in some cases, brain tissue with separable leptomeninges; the union never involves the foramen magnum, the skull base, the face or the vertebrae, except in craniorachipagus [24]. The Stone and Goodrich classification distinguishes partial forms, without shared dural venous sinuses, and total forms, with shared sinuses and greater cerebral distortion due to compression; within these, angular (longitudinal angle between the twins less than 140°) and vertical forms, the latter subdivided according to facial rotation (type I below 40°, type II between 140° and 180°, type III intermediate) [27]. In a review of 64 pairs of craniopagus twins, just over half were total vertical, almost one third total angular and one sixth partial; about 30% had shared or fused brain tissue, and a similar proportion of total angular twins shared the posterior fossa [27]. Craniopagus twins account for about 3.4% of conjoined twins [29]. Pygopagus twins frequently share the dural sac and the terminal spinal cord, including the conus medullaris and the filum terminale, and non-parasitic rachipagus twins are exceptional, with only two published cases, both with cranial union [24].

3.2. Associated malformations in conjoined twins

Excluding defects of the site of union itself, 10–20% of conjoined twins have major early defects, often discordant between the two twins [2]. In the ICBDSR, there were anomalies unrelated to the union in 115 of 182 pairs with information (63.2%); among 111 malformations described in 73 pairs, the most frequent were genitourinary (19.8%), musculoskeletal (12.6%), neural tube defects, facial clefts and gastrointestinal atresias (9.9% each), heart defects and limb reduction defects (6.3% each), hydrocephalus and abdominal wall defects (3.6% each) [7]. Neural tube defects exceeded 15% in parapagus dicephalus and diprosopus [7]. In the North American registry of 1970–1977, many conjoined twins had defects unrelated to the union, mainly neural tube defects and orofacial clefts [30].

Heart defects are the main prognostic determinant of the thoracic types. In São Paulo, 91.6% of the 36 pairs assessed prenatally had a heart defect, and there were other malformations in 61.8% (limbs 36.1%, abdominal wall 25.0%, cleft lip or palate 13.9%, diaphragmatic hernia 5.5%) [31]. In Philadelphia, 11 of 14 pairs diagnosed prenatally had cardiac malformations, 4 congenital diaphragmatic hernia, 2 abdominal wall defects and 2 imperforate anus [16]. In a series of 14 cases from San Francisco, prenatal ultrasound showed a shared heart in 9 (64%), and two omphalopagus pairs with separate hearts had severe heart disease [32].

3.3. Natural history of conjoined twins

The natural history is dominated by fetal and neonatal mortality. Boer and colleagues, citing earlier series, report that about 30% die in utero, 40–60% are stillborn and 35% survive one day [24]. In the review by Pajkrt and Jauniaux, when parents chose to continue the pregnancy without intervention, half of the fetuses died in utero and a further 44% in the neonatal period [33]. In the series of the Estudio Colaborativo Español de Malformaciones Congénitas (ECEMC), the frequency of conjoined twins among stillbirths (44.72 per 100,000) was 99 times higher than that observed among live births [34]. Among the 379 ICBDSR pairs with known outcome, 45.6% were live births, 27.2% stillbirths and 27.2% terminations of pregnancy for medical reasons (TOPMR) [7]. Among live births with data, 76.3% were born preterm and 39.0% had low birth weight [7]. After prenatal diagnosis in a series of 14 cases from a referral centre cited by ISUOG, 20% of parents opted for TOPMR and 10% of fetuses died in utero; among continued pregnancies, survival to discharge was about 25%, almost always with significant morbidity [12].

The cross-circulation persists after birth. In a referral centre in Riyadh, 7 of 10 pairs (70%) assessed between 2021 and 2023 had signs of extrauterine twin-to-twin transfusion syndrome: nutritional imbalance (the donor twin eats more and grows less), passage of drugs and fluids from one twin to the other and, in the two craniopagus pairs, haemodynamic instability with reversal of donor and recipient roles between the stages of separation, polyuria and hypertension in the recipient and renal cortical necrosis with anuria in the donor [35]. Donor twins had greater morbidity and mortality [35].

3.4. Heteropagus twins

In heteropagus twins, the autosite is usually a viable newborn, and the parasite contains limbs, pelvis, spinal segments, bowel or, rarely, a rudimentary heart and brain tissue [3]. In Spencer's review of 157 cases, the most frequent types were omphalopagus (30.6%), pygopagus, ischiopagus and rachipagus, and the male-to-female sex ratio was 1:1.04 [3]. In the systematic review by Mathur and colleagues, which brought together 120 cases published between 2001 and 2021, rachipagus (41.7%) and omphalopagus (38.3%) predominated; there were limbs in 75 cases, without musculature or capacity for movement, which is attributed to lack of innervation [3]. The autosite had congenital heart disease in 17 of 120 cases (14.2%; 14 omphalopagus and 3 rachipagus; 6 severe), omphalocele in 29 (28 omphalopagus) and meningomyelocele in 38, as well as tethered cord, dysraphism, diplomyelia and diastematomyelia [3]. Bony or visceral connections with the autosite, considered rare, were present in 12 cases (10%): bony or cartilaginous in 6, hepatobiliary in 3 and intestinal or bladder connections in 3 [3]. Spencer found a hypoplastic heart in 5 parasites and hypoplastic brain tissue in 9; since then, few parasites with a rudimentary heart have been described [3]. The parasite may cause respiratory distress and limit the growth of the autosite and, when poorly vascularised, become a focus of infection [3]. Published mortality between 2001 and 2021 was 12 of 120 cases, 8 from cardiac causes and 3 from sepsis [3].

3.5. TRAP sequence

The acardiac twin is not viable, but it threatens the pregnancy. The classic morphological classification describes the acardius acephalus (60–75%; developed pelvis and lower limbs, without head, thoracic organs and upper limbs), the anceps (about 10%; recognisable body and limbs, rudimentary head and face), the acormus (about 5%; cephalic pole only, attached to the placenta directly or by the cord) and the amorphus (about 20%; shapeless mass), with no prognostic value [8]. Figure 3 in Smith illustrates an acardius amorphus partly embedded in the placenta, with the arterio-arterial and veno-venous anastomoses, and an acardiac twin with upper limb deficiency and craniofacial disruption, with relative preservation of the lower half [2].

Perinatal mortality of the untreated pump twin may reach 55%: in a series of 49 pregnancies collected by Moore, Gale and Benirschke (1990), mean gestational age at delivery was 29 ± 7.3 weeks, mean weight of the pump twin 1378 g and of the acardiac twin 651 g; when the weight ratio between acardiac and pump twin exceeded 70% (25% of cases), preterm birth occurred in 90%, polyhydramnios in 40% and congestive heart failure in 30%, compared with 75%, 30% and 10% with lower ratios [36]. First-trimester diagnoses revealed high early mortality: in 24 pregnancies in which intervention was planned for 16–18 weeks, the pump twin died spontaneously in 8 (33%), flow to the acardiac twin stopped spontaneously in 5 (21%) and persisted in 11 (46%) [37]. In the Fetal Medicine Foundation series, 18 of 30 cases (60%) diagnosed at 11–14 weeks had spontaneous cessation of flow before the planned intervention, and in 11 of these (61.1%) the pump twin died or sustained brain injury [38]. ISUOG summarises these data as a risk of death of the pump twin of up to 30% by 18 weeks under expectant management [12]. At St George's, London, the 6 cases managed expectantly ended in intrauterine death at a median of 14+4 weeks [39].

The most recent Chinese studies, published in 2026, quantified the natural history in larger cohorts. In 116 pregnancies managed expectantly, only 25.0% had a favourable outcome, and pump twin survival varied with the structural development of the acardiac twin, from 66.7% in amorphous to 15.0% in hemiacardiac twins [40]. In another cohort of 117 monochorionic diamniotic pregnancies, treated or not, overall pump twin survival was 65.8% [41].

3.6. Other relevant monochorionic complications

Twin-to-twin transfusion through arteriovenous anastomoses produces a small, anaemic, hypovolaemic and oligohydramniotic donor and a large, polycythaemic, hypervolaemic and polyhydramniotic recipient, with enlarged kidneys and heart; Tan and colleagues found size and haematocrit discordance at birth in 18% of monozygotic twins [2]. Twin-to-twin transfusion syndrome and TAPS enter the differential diagnosis. The in utero death of a monozygotic twin exposes the survivor to hypoperfusion and hypoxia, with disseminated intravascular coagulation, aplasia cutis, porencephalic cyst to hydranencephaly, limb amputation, intestinal atresia and gastroschisis; in the Collaborative Perinatal Project (50,000 deliveries), about 3% of monozygotic twins near term had a dead co-twin and about one third of the survivors, or 1% of monozygotic births, had severe brain injury [2]. A 2026 meta-analysis of 311 survivors of spontaneous single fetal death in monochorionic pregnancies found brain injury in 27% (95% CI 18–37%) and neurodevelopmental impairment in 6% (95% CI 3–11%), the latter in about two thirds of those with brain injury [42]. These data do not include TRAP, but they underpin surveillance of the surviving twin when the co-twin dies from another cause.

3.7. Fetus in fetu

Fetus in fetu presents as an abdominal or retroperitoneal mass, sometimes already identified on prenatal ultrasound, in newborns, infants, children and exceptionally in adults [6, 15]. In a newborn from Lisbon, the mass compressed the left kidney and, after excision, weighed 8 g and contained an amniotic sac, rudimentary cord, two rudimentary limbs, vertebral bodies, brain, choroid plexus, stomach, duodenum, bowel, adrenal glands, respiratory tissue, spleen, lymphoid tissue, a single-chambered heart and kidney [10].

4. Clinical Recognition and Warning Signs

4.1. When to suspect in the prenatal period

Suspicion begins with the determination of chorionicity and amnionicity in the first trimester. Any monochorionic monoamniotic pregnancy should be referred to a tertiary centre, and the absence of an intertwin membrane is confirmed by transvaginal ultrasound and by demonstration of cord entanglement, almost universal in this situation, with two arterial waveforms of different rates in the same pulsed Doppler window [12]. Conjoined twins are suggested by the close and fixed apposition of the two bodies, with fusion of the skin lines at one point, in a monoamniotic pregnancy [12]. Before 10 weeks false positives are frequent, because fetal movements are limited and monoamniotic twins may appear joined [33].

The TRAP sequence should be considered whenever a monochorionic pregnancy has a fetus with obvious morphological anomalies, large biometric discrepancy (particularly in abdominal circumference), absence of a normal heart, subcutaneous oedema and fluid collections [8]. A monochorionic twin considered dead but which continues to grow, or in which Doppler shows persistent intrafetal flow, should raise the suspicion of TRAP [8]. Heteropagus twins may be labelled prenatally as meningomyelocele, spina bifida or omphalocele and only after birth reveal a rachipagus or omphalopagus parasite; in an Indian series, in 4 of 6 cases the pregnant women had prenatal care and the diagnosis of twinning was not made [3]. Three-dimensional ultrasound can distinguish an epigastric heteropagus twin from TRAP when two-dimensional ultrasound cannot [17].

4.2. Warning and emergency signs

In the pump twin, signs of poor prognosis are heart failure (hydrops, polyhydramnios), delivery before 32 weeks, an acardiac-to-pump weight ratio greater than 70%, discrepancy in umbilical vein diameter between pump and acardiac twin, and an acardiac twin with developed body and upper limbs [8]. The 2026 review by Zargarzadeh and colleagues adds a reversed a-wave in the ductus venosus and significant polyhydramnios as indications for intervention [43]. Ultrasound and Doppler surveillance does not prevent sudden death of the pump twin [12].

In conjoined twins, the death or deterioration of one of the twins and life-threatening correctable anomalies constitute emergencies, which may require emergency separation, with worse results than elective separation [19, 25]. In the delivery room, conjoined twins often need respiratory support: in a Philadelphia series from 2013–2025, 75% received continuous positive airway pressure, 67% positive-pressure ventilation and 25% intubation [44]. In heteropagus twins, respiratory distress, compression and infection of a poorly vascularised parasite justify early surgery [3].

4.3. After birth

A newborn with a supernumerary limb, a sacrococcygeal mass with limb elements or an epigastric mass with fetal structures should be assessed as a possible heteropagus twin [3, 45]. A calcified abdominal mass in an infant or child requires fetus in fetu, teratoma and other masses to be considered [15]. Examination of the surviving twin when the monozygotic co-twin died in utero looks for disruptive lesions (aplasia cutis, porencephaly, amputation, intestinal atresia) [2]. There is no newborn screening for these conditions.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Chorionicity and amnionicity

ISUOG recommends determining chorionicity before 13+6 weeks using as many ultrasound features as possible — the intertwin septum as a whole, with the lambda sign («twin peak») of dichorionic pregnancies or the T-sign of monochorionic pregnancies, membrane thickness and the number of placental masses (grade D) —, archiving the image that demonstrates it (good practice point), seeking a second opinion from a tertiary centre when it cannot be determined and, in case of doubt, classifying the pregnancy as monochorionic [12]. Amnionicity of monochorionic pregnancies can be determined from 8 weeks [12]. About 5% of apparently monochorionic twins were dizygotic in a Danish series, mainly after medically assisted reproduction [12]. The Oxford Desk Reference mentions six published cases of dizygotic twins with a monochorionic placenta, documented by fibroblast DNA [14].

5.2. Diagnosis and assessment of conjoined twins

First-trimester ultrasound diagnosis is now the norm [12]. The 11–14-week scan is sufficient in most cases; very early diagnosis and three-dimensional imaging in the first trimester add little practical information [33]. For pregnancies that continue, ISUOG recommends specialised imaging, ultrasound with or without MRI, to define the cardiovascular and other anatomy before delivery [12]. In the Philadelphia series, ultrasound, echocardiography and ultrafast fetal MRI correctly defined the shared anatomy in the 14 pairs, with diagnosis from 9 weeks (mean 20 weeks) [16]. In the San Francisco series, transvaginal ultrasound improved delineation of the union in two cases and CT confirmed the diagnosis in another two [32].

Echocardiography defines the degree of cardiac fusion, which decides the feasibility of separation. At Great Ormond Street Hospital, 23 pairs with thoracic fusion (1985–2004) were classified into four groups: separate hearts and pericardium (A, 5 pairs), separate hearts with a common pericardium (B, 7), fused atria and separate ventricles (C, 2) and fused atria and ventricles (D, 9) [20]. Prenatal and postnatal echocardiography correctly identified the degree of fusion in all pairs but one and the intracardiac anatomy in all, with three postnatal revisions of the prenatal diagnosis; all group D pairs had abnormal intracardiac anatomy [20].

Source: [20].

After birth, preoperative imaging is adapted to the zone of union: cardiac assessment in thoracic fusion; MRI and CT for organ position, shared viscera, skeleton and vascular anatomy; contrast studies of the digestive tract and genitourinary system; assessment of the anatomy, vascular supply and biliary drainage of the shared liver; and angiography to define the specific blood supply [46]. In São Paulo, hepatic angiography was used when CT angiography or MRI did not provide consistent information [25]. In craniopagus twins, neuroimaging studies the shared brain tissue, shared arteries and veins and bony and dural defects, and the Stone and Goodrich classification guides the surgical prognosis [27, 47]. Functional assessment of the cross-circulation, including pharmacological tests, informs anaesthesia [35, 48].

5.3. Diagnosis of the TRAP sequence

The pathognomonic finding is paradoxical circulation in the acardiac twin on colour Doppler: arterial blood reaches the acardiac twin through the cord, instead of leaving it, and travels along the abdominal aorta in a caudocranial direction, which may be visible from the first trimester [8]. The weight of the acardiac twin cannot be estimated with the usual biometric formulae; Moore and colleagues proposed the formula weight (g) = 1.2 × L² − 1.7 × L, where L is the largest dimension in centimetres [8, 36]. Wong and Sepulveda proposed a classification by the ratio of abdominal circumferences (type I less than 50%; type II equal to or greater than 50%) and by the presence (subtype b) or absence (subtype a) of signs of cardiac failure in the pump twin [8]. In an international survey, 90% of fetal therapy centres used echocardiography of the pump twin and 80% umbilical artery Doppler in the acardiac and the pump twin [49].

The ultrasound differential diagnosis includes intrauterine death of an anomalous monochorionic twin, which does not grow and has no flow, and intra-amniotic or placental tumours, excluded by the presence of a skeleton and of cord insertion [8].

5.4. Diagnosis of heteropagus twins and fetus in fetu

In heteropagus twins, prenatal diagnosis was made at a mean of 18 weeks (9–29 weeks) and allows planning of the mode of delivery and surgery; fetal MRI helped, in one case in the Mathur series, to plan immediate reduction of a common omphalocele [3]. After birth, initial radiography and ultrasound are complemented by contrast-enhanced CT and MRI to study vascular connections and exclude organ sharing, and by echocardiography in omphalopagus and thoracopagus twins; angiography is rarely necessary, and barium studies, hepatobiliary scintigraphy, urography or cystoscopy are used in selected cases [3]. In fetus in fetu, the vertebral column distinguishes it from teratoma, and cross-sectional imaging differentiates it from meconium peritonitis and abdominal ectopic pregnancy [15]. The absence of a visible vertebral axis on radiography or CT does not exclude the diagnosis, because the spine may not be calcified and may only be identified by the pathologist [18].

5.5. Genetic study and limitations

These conditions have no diagnostic genetic test. Genetic study serves other purposes: excluding aneuploidy when there are discordant anomalies, assessing zygosity and, rarely, investigating the origin of a parasite. ISUOG recommends, in monochorionic pregnancies discordant for a structural anomaly, ultrasound assessment in a tertiary centre with invasive chromosomal or genetic testing when indicated, noting that discordant aneuploidy in monochorionic twins is very rare but possible, and accepts amniocentesis of both sacs in discordant monochorionic diamniotic pregnancies (grade D) [12]. Cell-free fetal DNA screening for trisomy 21 is the most accurate method in twin pregnancy, with a detection rate possibly slightly lower than in singleton pregnancies (grade B) [12]. For zygosity, seven or more microsatellites (short tandem repeats) suffice in clinical practice; with a single placenta, it may be necessary to use a buccal swab or fibroblasts, because blood chimerism may exist, described in at least 8% of dizygotic twins [14]. A concordant result between twins or between host and mass does not exclude post-zygotic divergence in other tissues, and limited discordance does not prove dizygosity [24].

6. Differential Diagnosis

The differential diagnosis is organised along two axes: between the entities of the continuum of abnormal twinning themselves (symmetrical conjoined twins, heteropagus twins, acardiac twin and fetus in fetu) and between these and other monochorionic or malformative situations that mimic them. None of the entities has an associated gene, so the «gene» column of the table refers to the genetic differential diagnoses where they exist.

6.1. Heteropagus twin, acardiac twin and fetus in fetu

In Spencer's interpretation, the site of union and the degree of destruction of the defective embryo decide whether the result is an external parasite, a fetus in fetu, a teratoma or an acardiac twin [23]. In practice, the heteropagus twin is joined to the body of the autosite and supplied by its somatic vessels, whereas the acardiac twin is connected only through the placenta and is perfused through the cord [3, 8]. Prenatally, an epigastric heteropagus twin with pelvis and lower limbs may resemble TRAP, and three-dimensional ultrasound was decisive in a case in which two-dimensional ultrasound did not clarify the relationship between the two bodies [17]. Mathur and colleagues exclude fetus in fetu from their review of heteropagus twins, considering it a distinct entity, treated as a teratoma [3].

6.2. Fetus in fetu and teratoma

The central criterion is the presence of a vertebral column, often with other organs or limbs organised around it [15]. The absence of a visible spine on imaging does not exclude the diagnosis, because the spine may not be calcified [18]. Serum α-fetoprotein was used in the Lisbon case as a parameter before and after surgery (less than or equal to 16,000 IU/mL before and 8364 IU/mL after, with age reference values between 4 and 18,990 IU/mL) [10].

6.3. Conjoined twins and monoamniotic twins

The most common error in the first trimester is to diagnose as joined monoamniotic twins that are still not very mobile; confirmation after 10 weeks avoids hasty decisions [33]. Conversely, a monoamniotic pregnancy with entangled cords does not in itself have a worse prognosis: a systematic review of 114 monoamniotic pairs concluded that isolated entanglement does not contribute to perinatal morbidity and mortality [12].

7. Treatments and Risk Management Strategies

7.1. General principles and guideline recommendations

There is no targeted pharmacological treatment for any of the entities in this article; management is obstetric, fetal therapeutic and surgical. Two guidelines guide the prenatal part. The updated ISUOG recommendations (2025) cover the determination of chorionicity, surveillance of monochorionic pregnancies, selective feticide, TRAP, monoamniotic pregnancy and conjoined twins [12]. National Institute for Health and Care Excellence (NICE) guideline NG137, updated in April 2024, sets out the ultrasound schedule and the indications for seeking advice from a tertiary fetal medicine centre, which explicitly include TRAP, conjoined twins (twins or triplets) and pregnancies with a shared amnion [51].

7.2. Obstetric management of conjoined twins

Early diagnosis opens three options: continuing the pregnancy with a view to postnatal surgery, terminating the pregnancy where the law allows or, in triplet pregnancies, resorting to selective feticide of the joined pair [33]. The decision rests on the degree of organ sharing, above all of the heart: in San Francisco, 9 of 14 pairs had a shared heart, a situation in which postnatal correction is practically impossible, and 9 couples opted for TOPMR before 24 weeks, by the vaginal route [32]. In São Paulo, separation was considered unfeasible and the prognosis lethal in 30 of 36 pairs (83.3%), and 12 pregnancies with poor prognosis were terminated [31]. TOPMR rates among surveillance programmes range from 0% in countries where it is not permitted (Mexico, South America) to 81.1% in the French Centre-East region [7].

When the pregnancy continues, ISUOG recommends assessment in a fetal medicine referral centre with multidisciplinary counselling and delivery in a centre experienced in postnatal medical and surgical management, where the option of neonatal palliative care exists [12]. Vaginal delivery has been described, but the risk of dystocia, obstructed labour and uterine rupture makes elective caesarean section the rule [12]. In Philadelphia, the 10 live-born pairs in a series of 14 were delivered by caesarean section at a mean gestational age of 34 weeks [16]. In a pair in which a twin with a normal heart perfused the co-twin with a rudimentary heart, the team used the EXIT procedure (ex utero intrapartum treatment), with control of the airway and circulation before ligating the cord, followed by immediate separation, and the normal twin survived [16]. Resuscitation in the delivery room is complex and requires an experienced multidisciplinary team and an individualised plan rehearsed in simulation; in Philadelphia, between 2013 and 2025, 13 of 19 pairs received active resuscitation and 6 palliative care [44].

7.3. Surgical separation of conjoined twins

The possibility of separation depends above all on cardiac anatomy. With fused hearts, separation is rarely successful, and with separate hearts survival depends on the remaining viscera [52]. At Great Ormond Street Hospital, no pair with fused atria (group C) or with fused atria and ventricles (group D) survived, whereas in separated groups A to C 16 of 26 children survived [20].

The timing of separation divides centres. Great Ormond Street described three groups in 17 pairs: not operated on because of cardiac fusion or gross union (5 pairs, all deceased), emergency separation because of death or threat to one twin or because of a life-threatening correctable anomaly (7 pairs, 4 of 14 children surviving) and elective separation after investigation and planning (5 pairs, 8 of 10 survivors) [19]. In Philadelphia, in a 30-year series, operative survival was 50% in the neonatal period and 90% above 4 months, and the authors recommend delaying separation to 6–12 months when possible; there were 6 late deaths, up to 10 years later, from associated anomalies, mainly cardiac [53]. Spitz preferred to operate at around 3 months, when the body wall still expands rapidly, and the São Paulo group prefers 10 months, because of the greater functional reserve [25]. The 2026 systematic review on craniopagus twins associated success (both alive at 30 days) with the total vertical form in the Stone and Goodrich classification (90% success), staged surgery, the use of tissue expanders and the non-emergency nature of the procedure [29]. In total craniopagus, staged separation had significantly lower mortality than single-stage separation, and partial forms were separated earlier (6 versus 11 months) and with better results [27].

The figures are not comparable with one another, because the series differ in the point of inclusion (prenatal, birth or referral), in the selection of operated cases and in the period.

Preparation includes repeated anaesthesia and imaging, rehearsal of the surgical steps and duplication of teams. In São Paulo, four anaesthetists (two per twin) cannulated a central vein and the radial artery in each child, one surgical team performed the separation and a second team reconstructed the second twin in another theatre; anaesthesia lasted on average 8 h 45 min and surgery 6 h 52 min, longer in ischiopagus (11 h 35 min and 8 h 29 min) than in omphalopagus twins (5 h 12 min and 3 h 13 min) [25]. In ischiopagus twins, the liver was divided in the midline after confirming separate hila and hepatic veins, shared bowel required a colostomy or ileostomy in one of the twins when there was a single anus, crossed ureters (5 of 6 pairs) were reimplanted and the abdominal wall was closed with a flap from the third leg in tripus twins and with mesh [25]. The authors abandoned tissue expanders after skin necrosis in one case, citing expander complications in up to 57.2% of pairs in the literature, and recorded wound or urinary infection in 10 of 12 survivors (83.3%), late enteric fistulas in 2 and evisceration in 1 [25]. Conversely, expanders were associated with better results in craniopagus twins and were used successfully in Philadelphia [16, 29, 53]. The São Paulo group's opinion that a trained paediatric surgical team suffices and that the simultaneous participation of several specialties was «confusing» diverges from the recommendations for a multidisciplinary team in the other series and from ISUOG [12, 19, 25].

The cross-circulation requires each twin to be treated as an independent patient, with two anaesthetic teams, duplication of workstations and monitoring, and careful titration of drugs [48]. In the anaesthetic practice described in Riyadh, medication is often divided between the two twins; at an intubation in which one twin received three doses of ketamine, two of midazolam, one of fentanyl and one of rocuronium, it was the co-twin who became sedated [35]. Aminoglycosides require level monitoring in both twins: in two pygopagus twins treated with the same dose of amikacin (35 mg intravenously every 24 hours, about 14.2 mg/kg/day), peaks were 7.7 and 13.1 mg/L, and in a thoracopagus pair amikacin given to one twin only reached 10.9 mg/L in the untreated twin [56, 57]. These values describe exposure and do not constitute a recommended dosage.

7.4. Heteropagus twins

Management begins prenatally: the outcome of the autosite is generally favourable, which should be conveyed to parents to avoid unnecessary terminations, except in cases with severe heart disease in the autosite [3]. In the review of 120 cases, the mode of delivery was known in 63 (36 vaginal and 27 caesarean), and 10 of 11 cases diagnosed prenatally were born by caesarean section; weight alone did not distinguish vaginal from surgical deliveries, and the authors recommend deciding on the basis of anatomy, position and weight, considering caesarean section mandatory when the parasite has a head [3].

Surgical excision is indicated for aesthetic and social reasons, respiratory distress, compromised growth of the autosite and the risk of sepsis from a poorly vascularised parasite [3]. It is usually performed in a single stage, in the neonatal period, when tissues are more pliable and closure is easier, particularly with a coexisting omphalocele; in some cases, the external structures are removed first and the internal parasitic viscera later [3]. Exploration must be complete, because retained parasitic viscera caused intestinal obstruction 2 months and 17 years after the first operation, and there are reports of teratoma in retained remnants [3]. In the Cape Town series, all live-born heteropagus twins survived separation, and in a 2026 Indian series the 6 heteropagus twins were separated with one death from neonatal sepsis [45, 54].

7.5. TRAP sequence: principles and techniques

The aim is to preserve the pump twin and bring the pregnancy close to term by interrupting perfusion of the acardiac twin [8]. The first treatments were directed at the complications: digoxin and other inotropes for heart failure of the pump twin, indometacin and amniodrainage for polyhydramnios [8]. These approaches are now of historical interest and the sources consulted do not give a dosage for this indication. In 1989, Robie and colleagues performed a hysterotomy at 22 weeks with selective extraction of a 710 g acardiac twin, and the pump twin was born at 33 weeks weighing 2130 g; in the seven procedures of this type published between 1989 and 1992, there were two cases of maternal pulmonary oedema due to aggressive tocolysis and three placental abruptions [8].

Current techniques are divided into cord occlusion and intrafetal ablation. Cord occlusion has been performed by coil embolisation (Hamada, 1989), fetoscopic ligation, thrombogenic agents, monopolar or bipolar coagulation and fetoscopic laser coagulation with a neodymium-yttrium-aluminium-garnet laser (Nd:YAG; Ville, 1994); fetoscopy requires larger-calibre trocars, has about 10% technical failure and more premature rupture of membranes, infection and haemorrhage, and is difficult with an anterior placenta or oedematous, short cords [8]. Intrafetal ablation, directed at the pelvic vessels or the abdominal aorta of the acardiac twin, does not depend on the location of the placenta or the cord; it includes injection of absolute alcohol (Sepulveda, 1995; 20–22 G needle, with a risk of the sclerosant passing to the pump twin), monopolar diathermy (18 G needle), interstitial laser (18 G needle, Nd:YAG or diode laser, local anaesthesia) and radiofrequency ablation (14 G device with umbrella tines and automatic shut-off due to increased impedance) [8]. ISUOG also includes microwave ablation among the methods of selective feticide in monochorionic pregnancies and contraindicates potassium chloride, because of the risk to the co-twin [12].

The systematic review by Tan and Sepulveda (2003), with 71 cases, found pump twin survival of 76% and showed that intrafetal ablation, compared with cord occlusion, was associated with later delivery (37 versus 32 weeks), fewer technical failures (13% versus 35%), less delivery or rupture of membranes before 32 weeks (23% versus 58%) and more clinical success (77% versus 50%) [58]. The systematic review by Mone and colleagues (2016; 26 studies) concluded that intervention improves survival compared with conservative management (odds ratio 2.22; 95% CI 1.23–4.01), particularly with one or more poor prognostic factors (8.58; 1.47–49.96), and that ablation is superior to cord occlusion (9.84; 1.56–62.00), with insufficient data to define which factors should trigger intervention [59]. Today fetoscopy has been practically abandoned, and intrafetal laser and RFA are the most widely used techniques [8]. In the St George's series, neonatal survival was similar with RFA and intrafetal laser (85% versus 82%), but premature rupture of membranes before 32 weeks was more frequent with RFA (22% versus 7%) [8]. In an international survey, most centres in Europe and Latin America proposed intervention in all cases and preferred interstitial laser, North America preferred RFA, and the minimum gestational age for intervention was on average 13 weeks in Europe, earlier than in other regions [49].

7.6. TRAP sequence: timing of intervention

The optimal timing remains to be defined. Traditional intervention at 16–18 weeks assumed a lower risk of miscarriage after obliteration of the coelom, but exposes the pump twin to spontaneous death between early diagnosis and the procedure [8, 37]. ISUOG accepts both prophylactic treatment and serial surveillance with intervention when signs appear of cardiac overload in the pump twin, increased perfusion of the acardiac twin (including polyhydramnios) or growth of the mass, notes that there may be benefit from intervention before 16 weeks and that survival might improve with elective intervention at 12–14 weeks, and stresses the observational nature of this evidence (level 3) [12]. The rate of delivery before 32 weeks after treatment is around 10%, and the gestational age at intervention is inversely related to the gestational age at delivery [12, 38]. In Bonn, intrafetal laser before 14 weeks in 12 pregnancies caused no miscarriages or ruptures of membranes, but the pump twin died in 5 (41.7%) in the following 48–96 hours [50]; in Hamburg, in 12 pregnancies treated up to 14+3 weeks, there was one death (8.3%) and 11 live births at a median of 39+6 weeks [60]. The differences may reflect inclusion criteria, technique, gestational age and fetal size within the narrow window from 11 to 15 weeks [8]. To resolve the question, the TRAPIST randomised trial compares intervention at 12–14 weeks with intervention at 16–18 weeks; the ClinicalTrials.gov registration anticipated 126 participants and completion in June 2025, but the status has been «unknown» since July 2024 and no published results were found up to 29 October 2026 [12, 61]. There is also no consensus on the timing of delivery after treatment or surveillance, which should be individualised according to the success of treatment, Doppler findings and the cardiac stability of the pump twin [12].

None of these studies is randomised. The series differ in selection (referred cases, diagnosis in the first or second trimester), techniques and outcome definition, so survival rates cannot be compared directly with one another, and the early treatment series have 12 cases each. The systematic reviews aggregate series with probable publication bias.

7.7. TRAP in monoamniotic pregnancy and other situations

In about 5% of cases, TRAP occurs in a monoamniotic pregnancy; if the cord of the acardiac twin is long, it becomes entangled with that of the pump twin, and intrafetal ablation alone may leave the acardiac twin's cord constricting that of the pump twin, so cord coagulation (fetoscopic laser or bipolar) followed by transection is recommended, with pump twin survival of about 75% [8]. ISUOG recommends cord occlusion and transection in all selective reductions in monoamniotic pregnancies, with more premature rupture of membranes and earlier delivery than in diamniotic pregnancies [12]. Among children who survived after RFA in Japan, assessment at about 2 years and 5 months of 27 of the 32 survivors found no neurodevelopmental delay (median developmental quotient 111) [65].

7.8. Monoamniotic pregnancy

Monoamniotic pregnancies account for about 5% of monochorionic pregnancies; loss before 16 weeks may reach 50%, mainly due to anomalies and spontaneous miscarriage, and overall loss has fallen from 40% in the older literature to 10–15% in recent studies [12]. In a cohort of 98 monoamniotic pregnancies, perinatal mortality was 19% (17% excluding lethal anomalies), only 4% after 32 weeks, with twin-to-twin transfusion in 6% and brain injury in 5% [12]. ISUOG recommends caesarean section at 32–34 weeks (grade D) and NICE planned delivery between 32+0 and 33+6 weeks, with routine admission of the newborns to the neonatal unit [12, 51]. Inpatient or outpatient surveillance remains under discussion: one meta-analysis found intrauterine death of 3% with admission and 7.4% as outpatients, but a multicentre cohort found no significant difference [12].

7.9. Drugs, regulation and perioperative use

The guidelines and reviews consulted describe no medicinal product targeted at the entities in this article or authorised for them by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA), and recommend no specific drug [8, 12, 51]. The regulatory table is therefore reduced to the practical consequence of that absence.

In the perioperative period of separation, tranexamic acid was used in a Portuguese case as part of blood management during division of the liver (150 mg bolus followed by 5 mg/kg/h), together with viscoelastic tests and a paediatric massive transfusion protocol [48]. This regimen describes one case and does not constitute a recommendation. In conjoined twins with cross-circulation, drugs with a narrow therapeutic margin, such as amikacin, require level measurement in both twins, and the administration of sedatives and neuromuscular blockers must take into account passage to the co-twin [35, 56, 57].

7.10. Developments in the last 12 months

Between November 2025 and October 2026, the literature brought mainly observational studies. In TRAP, a Chinese cohort with external validation proposed an acardiac/pump weight ratio below 0.295 after 14 weeks as a predictor of pump twin survival (retrospective human study) [41]; a new morphological classification into five types showed survival without treatment between 15.0% and 66.7% (retrospective human study) [40]; a Turkish series of 20 cases with RFA, laser, cord coagulation and microwave achieved 80% live births (series) [64]; and a 2026 narrative review summarised the decision factors and noted the lack of randomised trials [43]. In conjoined twins, the systematic review of 33 craniopagus separations identified factors associated with success (systematic review) [29], the Philadelphia series described delivery-room resuscitation with high survival after separation (series) [44], a series from Cameroon documented mortality of 76.5% in a low-resource setting (series) [55], two Turkish publications described amikacin pharmacokinetics with cross-circulation (review and case modelling) [56, 57] and a Lisbon group published the anaesthetic management of the elective separation of omphalopagus female twins (case report) [48]. In heteropagus twins, an Indian series of 6 cases with 3 to 8 years of follow-up confirmed the good prognosis of the autosite (series) [45]. There were no regulatory applications, opinions or authorisations, and the TRAPIST trial remains without results [61].

7.11. Ethics and shared decisions

Separation raises its own technical, legal and ethical questions [66]. Decisions not to separate, to separate as an emergency sacrificing one of the twins or to continue the pregnancy are taken with the parents and, in several centres, with ethics committees: in São Paulo, the decision not to operate on 9 pairs was taken with the parents and the ethics committee, one living pair was not separated because of parental refusal supported by the institutional ethics committee and the Regional Council of Medicine, and a craniopagus twin with microcephaly and sirenomelia was sacrificed at separation with family consent [25]. In heteropagus twins, early surgery may be necessary even with incomplete investigation when there is a risk of the child being abandoned, a situation documented in several cases [3].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk

The recurrence risk of conjoined twins is described as negligible [2]. The absence of familial cases in the 383 ICBDSR pairs and the absence of conjoined twins among about 1500 descendants of the Bunker brothers support this estimate [7]. For the combination of monozygotic twinning with an early malformation sequence, Smith considers the risk low to negligible, although the specific aetiology is unknown [2]. In heteropagus twins, the cases with consanguinity (3) and with a family history of twinning (4) among 120 published are too few to estimate a risk [3]. The sources consulted provide no validated numerical estimate of recurrence for any of the entities, and the absence of documented recurrence does not equate to zero risk. Recurrence of monozygotic twinning itself may occur in the rare families with apparently dominant transmission [2].

8.2. Medically assisted reproduction

Medically assisted reproduction increases monozygotic twinning: about 4-fold after in vitro fertilisation, and 5.6% with blastocyst transfer versus 2% with day-3 transfer in a 2003 series [14]. The increase is attributed, among other hypotheses, to damage to the zona pellucida and constriction of the inner cell mass during hatching [24]. Heteropagus twins have been published after medically assisted reproduction (2 cases in the 2001–2021 review) [3]. The data do not allow the risk of conjoined twins or TRAP to be quantified by assisted reproduction technique. Van Gemert and colleagues consider assisted reproduction one of the factors that raise the estimated incidence of TRAP to 1 in 9500 to 11,000 pregnancies [13].

8.3. Prenatal diagnosis and decisions in pregnancy

Prenatal counselling focuses on the prognosis of each twin and the options: surveillance, fetal therapy, termination where permitted, selective feticide in higher-order multiple pregnancies and the delivery plan [12, 33]. In conjoined twins, counselling depends on the degree of cardiac and hepatic fusion and should be provided in a fetal medicine centre with a multidisciplinary team [12, 20]. In heteropagus twins, the prognosis of the autosite is generally favourable, except with severe heart disease, and this should be explained to the parents [3]. In TRAP, counselling includes the early spontaneous mortality of the pump twin, the efficacy of ablation techniques and the uncertainty about the timing of intervention [12, 37]. When there are discordant anomalies in a monochorionic pregnancy, amniocentesis of both sacs may be considered [12].

8.4. Zygosity and chimerism

In same-sex twins, zygosity can be documented at birth with cord blood, and the Oxford Desk Reference suggests considering such documentation in all same-sex dichorionic twins; with a single placenta, DNA from a buccal swab or fibroblasts avoids the effect of blood chimerism [14]. This information is of value to the family and for future studies, but does not alter the recurrence risk of these entities.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence of conjoined twins by region

The classic estimate of 1 in 50,000 to 1 in 100,000 births was refined by the ICBDSR study, which found 1.47 per 100,000 births (95% CI 1.32–1.62), about 1 in 68,000, with wide variation between surveillance programmes [7]. Mian and colleagues estimate 1 in 50,000 births and, given the proportion of stillbirths, about 1 in 200,000 live births [66]. The differences depend on population size, on the inclusion of stillbirths, spontaneous miscarriages and TOPMR, and on the registration of terminations [7].

Source: [7]. Birth prevalence, including live births, stillbirths and, where recorded, TOPMR.

Finland, South America (ECLAMC, based in Rio de Janeiro) and Mexico had prevalences significantly above the mean, and North-East Italy, Campania, Spain and Texas significantly below [7]. Prevalence was higher in the Latin American group than in the Anglo-Saxon or Caucasian (odds ratio 1.51), Chinese (1.65) and Latin European (2.50) groups, which the authors attribute in part to under-registration of TOPMR in the European programmes [7]. There was a non-significant upward trend in the ECLAMC between 1987 and 2006 and a downward trend in the remaining programmes [7].

In the USA, the Birth Defects Monitoring Program recorded 81 pairs in 7,903,000 births between 1970 and 1977 (10.25 per million), with a predominance of females and of non-white births and no effect of maternal age [30]. In Spain, the ECEMC recorded 0.70 per 100,000 births between 1980 and 2006; the frequency fell from 1.47 per 100,000 in 1980–1985, when TOPMR was illegal, to 0.09 per 100,000 in 1996–2006, a more than 16-fold fall attributed to termination of affected fetuses, and the authors regard the 1980–1985 period as the baseline value for the population [34]. In Spain, thoracopagus twins accounted for 58.8% of symmetrical twins, with 0.44 per 100,000 births [34]. These values measure birth prevalence in monitored populations and not incidence at conception, nor the national prevalence of countries that lack a complete registry.

9.2. Sex, types and maternal characteristics

Conjoined twins are more frequent in females: in the ICBDSR, 218 female and 108 male pairs (odds ratio 2.23; 95% CI 1.76–2.83), with a marked female predominance in thoracopagus twins (ratio 3.27) and a male predominance in parapagus and parasitic twins [7]. Mian and colleagues report a female-to-male ratio of 3:1, and the Oxford Desk Reference states that 75% of conjoined twins are female [14, 66]. In heteropagus twins, the female predominance is less marked (ratio 1:1.04 in Spencer) and, in the 2001–2021 review, there were 59 male and 43 female cases [3]. Maternal age showed no association with conjoined twins; 19.8% of multiparous mothers had previous spontaneous miscarriages, and none of 164 women with information had taken folic acid [7].

9.3. Heteropagus twins, TRAP and fetus in fetu

The incidence of heteropagus twins is estimated at about 1 per million live births, and a 2026 Indian series cites 1 in 1 to 2 million [4, 45]. Most published cases come from India and South Africa, which has led to hypotheses of a genetic, environmental or nutritional contribution (folate deficiency in rachipagus twins), not demonstrated [3]. The classic incidence of TRAP, of about 1% of monochorionic pregnancies (1 in 100 monozygotic pregnancies, according to Moore) and 1 in 35,000 births, comes from studies from 1944 and 1953 [13, 36]; the current estimate, including cases of early cessation of acardiac development and the effect of assisted reproduction, is 2.6% of monochorionic pregnancies and 1 in 9500 to 11,000 pregnancies, and ISUOG uses 2.5% and 1 in 15,000 [12, 13]. Orphanet classifies the prevalence of fetus in fetu as between 1 and 9 per million [6].

9.4. Portugal and Brazil

The sources consulted do not include Portuguese prevalence studies. Published reports include a case of fetus in fetu treated at Hospital de São Francisco Xavier, in Lisbon, and the elective separation of omphalopagus female twins at the Unidade Local de Saúde de São José, in Lisbon [10, 48]. In Brazil, the ECLAMC contributed 108 pairs to the ICBDSR study (South America, 2.37 per 100,000 births), and São Paulo has two clinical series: 36 pregnancies at the Hospital das Clínicas, with overall survival of 8.3%, and 21 pairs at the Instituto da Criança, with survival of 66.7% after surgery [7, 25, 31]. The Instituto da Criança group considers it likely that the incidence of conjoined twins in Brazil is higher than in many developed countries, because termination of pregnancy is not generally legal; the ICBDSR recorded that TOPMR was not permitted in the countries covered by the ECLAMC [7, 25]. In low-resource countries, mortality remains high because of late referral and lack of neonatal transport and intensive care, as shown by the series from Cameroon (76.5%) [55].

9.5. Networks and resources

There is no European Reference Network specific to conjoined twins. ERN ITHACA, dedicated to rare malformation syndromes, is the closest network for complex malformations, and ERN CRANIO is relevant for craniopagus and cephalopagus twins [21, 22]. In the United Kingdom, the Oxford Desk Reference lists the Multiple Births Foundation and Tamba (Twins and Multiple Births Association) as support groups [14]; Twins Trust, a charity registered in England, Wales and Scotland, currently supports families of twins and triplets [67].

10. Illustrative Clinical Case

Godinho, Paulos and Pinto Carneiro, anaesthetists at the Unidade Local de Saúde de São José – Centro Hospitalar Universitário de Lisboa Central, published in 2026 the anaesthetic management of the elective separation of two 3-year-old omphalopagus female twins [48]. The diagnosis of conjoined twinning had been made at around 5 months of gestation, in a pregnancy with limited antenatal care, and delivery was by caesarean section under general anaesthesia, without immediate neonatal complications; both children had age-appropriate psychomotor development [48]. The union extended from the costal margin to the perineum, as shown in Figure 1 of the article, which documents the fusion of the anterior abdominal wall before surgery (https://pmc.ncbi.nlm.nih.gov/articles/PMC12831162/figure/FIG1/) [48]. The heart and lungs were independent and structurally normal, and the twins shared hepatic parenchyma with capsular fusion; contrast-enhanced CT and selective hepatic angiography showed normal individual hepatic vasculature, without aberrant or dominant vascular connections, and a pharmacological cross-circulation test showed minimal haemodynamic interaction [48]. Both had recurrent urinary tract infections and iron-deficiency anaemia, corrected before surgery in collaboration with transfusion medicine (preoperative haemoglobin 11.6 g/dL), and were classified as American Society of Anesthesiologists (ASA) class III [48].

Preparation included two independent anaesthetic teams, complete duplication of anaesthetic workstations, monitors, drugs and infusion pumps, colour coding to avoid mix-ups of drugs, fluids or blood products, simulation rehearsals, reservation of red cell concentrate, plasma, platelets and fibrinogen, and a paediatric massive transfusion protocol, because losses exceeding one blood volume were anticipated during division of the liver [48]. Induction was sequential, with sevoflurane, followed by target-controlled infusion of propofol and remifentanil; the neuromuscular blocker was given to the first twin and avoided in the second as a precaution given the cross-circulation; monitoring included invasive arterial pressure, bispectral index, near-infrared spectroscopy, temperature, blood gases and urine output [48]. Tranexamic acid was started before division of the hepatic parenchyma, and surgery lasted 18 hours in total, with estimated blood loss of about 200 mL, minimum haemoglobin of 7.5 and 8 g/dL, maximum lactate of 2 and 1 mmol/L and no need for vasopressors [48].

Postoperatively, both children stayed 25 days in paediatric intensive care. One was extubated on the third day; the other required 14 days of ventilation for peritonitis due to Serratia spp. and Pseudomonas aeruginosa, resolved with targeted antibiotic therapy, and received a further 4 units of red cell concentrate and 1 of plasma, with minimum haemoglobin of 6.2 g/dL [48]. Both had transient prerenal acute kidney injury and a rise in aminotransferases up to about 220–260 U/L, with progressive decline, without biliary complications or coagulopathy [48].

The case illustrates the principles described in the larger series: elective separation after complete anatomical assessment, with independent hearts as a favourable condition, two teams, attention to the cross-circulation and anticipatory management of hepatic haemorrhage [19, 20, 35]. The age of 3 years is later than that preferred by the London (about 3 months), Philadelphia (6–12 months) and São Paulo (about 10 months) series, and the authors cite as advantages of later separation the greater physiological reserve and the possibility of complete preoperative optimisation [25, 48, 53]. The anaesthetic regimen and doses in the report describe one case and are not presented as routine.

11. Prognosis and Long-Term Follow-up

11.1. Conjoined twins

The prognosis depends on the type of union, cardiac fusion, the timing of surgery and the care setting. Without separation, fetal and neonatal mortality is very high: half die in utero and a further 44% in the neonatal period when the pregnancy is continued without intervention [33]. With atrial or ventricular fusion, no pair survived separation in the Great Ormond Street series [20]. In the surgical series, survival of operated children ranges from about 65% to 90%, according to the series, age at surgery and elective nature, and emergency separation has worse results [19, 25, 53, 54]. Overall survival of all pairs diagnosed prenatally is low: 18% of children in Philadelphia and 8.3% in São Paulo [16, 31]. Survivors of separation have frequent morbidity — wound and urinary infections, fistulas, hernias, abdominal wall deficits and stomas — and may die late from associated heart disease, up to 10 years after surgery [25, 53]. In craniopagus twins, partial forms have better results than total forms, and staged separation reduces mortality [27, 29].

11.2. Heteropagus twins

The autosite generally has a good prognosis, determined mainly by associated heart disease; published mortality between 2001 and 2021 was 12 of 120 cases, 8 from cardiac causes and 3 from sepsis, with a downward trend in the last decade [3]. In the Mathur series, 5 of the 6 autosites were well at a median follow-up of 13 years [3]. Late complications include incisional hernia, obstruction by retained parasitic viscera and teratoma in residual tissue [3]. Rachipagus autosites with meningomyelocele or tethered cord require the neurosurgical and urological follow-up appropriate to those conditions [3].

11.3. TRAP sequence

Without treatment, perinatal mortality of the pump twin reaches 55% in the historical series, and the risk of death by 18 weeks is as high as 30% [12, 36]. With treatment, pump twin survival is around 80% [12, 62]. In children treated with RFA, assessment at about 2 years found no neurodevelopmental delay [65]. The sources consulted provide no equivalent neurodevelopmental data after early intrafetal laser; the registered primary outcome of TRAPIST is neonatal survival with delivery from 34 weeks [61].

11.4. Surveillance table

12. Summary and Final Considerations

Conjoined twins, heteropagus twins, the acardiac twin and fetus in fetu are variants of abnormal monochorionic monozygotic twinning, with no identified gene and a recurrence risk described as negligible. The birth prevalence of conjoined twins is about 1.5 per 100,000 births, with a female predominance and wide variation between registries, partly explained by termination of pregnancy; heteropagus twins occur in about 1 per million live births, and TRAP in 2.5% of monochorionic pregnancies.

Diagnosis is by ultrasound and begins with the determination of chorionicity and amnionicity in the first trimester. In conjoined twins, echocardiography and fetal MRI define organ sharing, and cardiac fusion decides the feasibility of separation; delivery is by elective caesarean section in an experienced centre, with the option of palliative care. Elective separation, planned by experienced teams, has much higher survival than emergency separation, and the cross-circulation conditions anaesthesia and pharmacotherapy. In heteropagus twins, the autosite generally has a good prognosis, and complete neonatal excision of the parasite avoids late complications. In TRAP, interruption of perfusion of the acardiac twin by intrafetal techniques raises pump twin survival to about 80%; the ideal timing of intervention still lacks an answer from a randomised trial, and the ultrasound predictors published in 2026 await prospective validation.

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