Triploidy and Diploid/Triploid Mixoploidy

Constitutional polyploidy with a complete extra haploid set (69 chromosomes), of paternal (diandric) or maternal (digynic) origin, which gives rise to distinct fetal and placental phenotypes, partial hydatidiform mole and maternal complications; in the mosaic form with a diploid cell line (46/69), it is compatible with postnatal survival.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Historical overview

The first description of a human malformation syndrome associated with a 69-chromosome complement was published by Böök and Santesson in 1960 in the Lancet, and the cytogenetic follow-up of the patient and family was reported by the same authors, with Masterson, in 1962 [33, 34]. In 1964, Ferrier and colleagues linked congenital body asymmetry to diploid-triploid mosaicism, opening the way to the delineation of the mosaic form, later characterised by Tharapel and colleagues (1983) and by Graham and colleagues (1981), who described the pattern in fibroblast culture and the resemblance to Silver-Russell syndrome [3, 35, 36].

The relationship between the parental origin of the extra haploid set and the placental phenotype was established by Jacobs, Szulman and colleagues. In a study of 1500 consecutive spontaneous miscarriages in Hawaii, they identified 106 triploids and, using cytogenetic heteromorphisms, showed that all 51 triploids of paternal origin in which a pathological diagnosis was possible were partial moles, whereas only 3 of 15 of maternal origin had molar changes; mean gestational age was 122 days in the paternal and 74 days in the maternal cases, a difference the authors attributed to retention of the molar placenta after fetal death [37]. In 1991, McFadden and Kalousek described two distinct fetal and placental phenotypes in 19 fetuses, correlated with parental origin, and proposed a genomic imprinting effect by analogy with mouse embryos; in 1993, genotyping with DNA polymorphisms confirmed the correspondence between digynic origin and the type II phenotype and between diandric origin and type I [38, 39].

Molecular studies from 2000 to 2002 clarified the mechanisms. Zaragoza and colleagues, in 91 triploid miscarriages from Pittsburgh and Cleveland, found a predominance of diandry due to dispermy and maternal errors mainly in meiosis II, and showed that only a fraction of the paternal cases had a partial mole phenotype [40]. Baumer and colleagues, in 25 probands from Zurich, and McFadden and colleagues, using pericentromeric markers in 14 diandric cases, concluded that diandry results from dispermy, with no evidence of a diploid sperm [41, 42]. Population-based and fetal medicine cohorts from Denmark (158 pregnancies, 1986–2010), Amsterdam (120 pregnancies, 2000–2018) and Warsaw (107 samples) then quantified the ultrasound and biochemical phenotype and the maternal complications by origin [19, 43, 44].

1.2. Nomenclature and reclassification

Nomenclature alternates among three equivalent systems. Designation by origin (diandric, digynic) is preferred; designation by phenotype (type I for diandric, type II for digynic) comes from McFadden and Kalousek; and notation by parental contribution (PPM, two paternal sets and one maternal; MMP, two maternal and one paternal; P1P2M when the two paternal sets differ, indicating dispermy) is used in genotyping studies [26, 38, 43]. Daniel and colleagues proposed broadening the type I definition to "well-grown fetus to moderate symmetrical FGR", because half of the diandric fetuses in their series had mild to moderate symmetrical growth restriction [45].

Partial hydatidiform mole is a histopathological entity, not a synonym for triploidy: about 90% of PHMs are diandric triploids, but not all triploid or tetraploid pregnancies are partial moles, and the diagnosis requires trophoblastic hyperplasia [25]. The 5th edition of the World Health Organization (WHO) classification of female genital tumours introduced the category of non-molar abnormal villous lesions, which includes trisomies and digynic triploidy, with the same low GTN risk as other non-molar conceptions [23]. The term "mixoploidy" refers to the coexistence of cell lines with different numbers of chromosome sets (here 46 and 69), whatever the mechanism, and encompasses true mosaicism (a single zygote) and chimaerism (two zygotes) [46].

1.3. Definition of the entities covered

Complete (non-mosaic) triploidy: karyotype 69,XXX, 69,XXY or 69,XYY in all cells analysed, with phenotype determined mainly by the origin of the extra set; it is usually lethal in the prenatal period [1, 4]. Diandric triploidy: two paternal sets and one maternal set, almost always due to dispermy; associated with a large placenta and partial mole in a proportion of cases [40, 43]. Digynic triploidy: two maternal sets and one paternal set, due to failure of meiosis II or, less often, meiosis I; associated with asymmetric FGR and a small non-molar placenta [19, 41]. Partial hydatidiform mole: conception with embryonic or fetal tissue, focal villous hydrops and trophoblastic hyperplasia, generally diandric triploid [2, 25]. Diploid/triploid mosaicism: coexistence of 46 and 69 lines, with possible postnatal phenotype and diagnosis dependent on the tissue analysed [3, 24]. Diploid/triploid mixoploidy is covered in the dedicated subsections of each section. Triploidy is one of the causes of anembryonic pregnancy and of sporadic pregnancy loss of chromosomal cause.

2. Molecular Genetics and Pathophysiology

2.1. Nature of the abnormality

Triploidy is a polyploidy: the conceptus has one complete extra haploid set of 23 chromosomes, for a total of 69, rather than an aneuploidy of a single chromosome, so that all autosomes are present in three copies and the relative dosage among autosomes is preserved [1, 47]. Unlike trisomies due to non-disjunction, advanced maternal age is not a risk factor; EUROCAT recorded 20% of mothers aged 35 years or older, with no association with maternal age, and the study by Wyrobek and colleagues found no association with paternal age [11, 12, 48]. The phenotype results less from dosage excess than from imbalance between parental genomes at genes subject to genomic imprinting: the paternal genome favours development of the trophoblast and placenta, and the maternal genome that of the embryo, reproducing in humans the observations in mouse embryos [15, 38, 49].

2.2. Diandric triploidy: dispermy

In diandric triploidy the conceptus receives two paternal sets and one maternal set. Oxford Desk Reference describes it as the result of simultaneous fertilisation of an oocyte by two sperm, and Smith attributes dispermy to failure of the zona reaction that normally prevents polyspermy, that is, to a maternal factor [3, 4]. Orphanet and the 2005 Unique guide retain the alternative of a diploid sperm arising from a meiotic error [2, 30]. Earlier studies estimated about two-thirds dispermy and one-third paternal meiotic error, but with markers very close to the centromere, all 14 cases of McFadden and colleagues (2002) and the 5 diandric cases of Baumer and colleagues (2000) resulted from dispermy; Zaragoza and colleagues reached the same conclusion in 91 miscarriages [40–42]. Among the 154 triploid conceptions with vesicular villi from western Denmark, all were P1P2M, that is, with two different paternal contributions, confirming dispermy [26]. In the series of products of conception audited by Joyce and colleagues with short tandem repeat (STR) markers, all diandric partial moles were dispermic [50].

2.3. Digynic triploidy: errors of maternal meiosis

In digynic triploidy the oocyte retains an extra chromosome set. The most frequently cited mechanism is non-extrusion or incorporation of the second polar body, that is, failure of meiosis II, and Smith cites meiosis II failure producing a diploid oocyte as one of the two most common mechanisms [3, 4]. Genotyping with pericentromeric markers shows, however, that meiosis I also contributes: in 20 digynic cases from Zurich, the error was in meiosis I in 10 and in meiosis II in 10 [41]. Zaragoza and colleagues found mainly meiosis II errors [40]. In one of the digynic miscarriages studied by Liang and colleagues, SNP microarray showed, in addition to the meiosis II failure demonstrated by STR, a meiosis I abnormality, with segregation of both maternal homologues [10]. Hasegawa and colleagues demonstrated maternal meiosis II non-disjunction in a 69,XXX infant who survived 46 days, and Fryns and colleagues, in a 69,XXX infant who lived two months, inferred non-extrusion of the second polar body from a 9qh heteromorphism [51, 52].

2.4. Sex chromosomes and X inactivation

Smith reports about 60% 69,XXY karyotypes, with nearly all the rest 69,XXX, and notes that it is not unusual for more than one X to remain active in triploidy; the Unique guide states that about two-thirds of triploid pregnancies are of male fetuses [3, 30]. Data from genotyped cohorts are more detailed. Among the 154 diandric triploidies with vesicular villi from Denmark, the XXX:XXY:XYY ratio was 5.7:6.9:1.0, consistent with selection against 69,XYY [26]. In the Danish cohort of 158 pregnancies, PPM cases were 43% 69,XXX, 51% 69,XXY and 6% 69,XYY, and MMP cases were similarly distributed among the possible karyotypes [43]. In Warsaw, the 107 samples comprised 52 69,XXX, 54 69,XXY and one 69,XYY; 69,XXY accounted for 62.5% of diandric and 42.4% of digynic cases [44]. Graham and colleagues found two active X chromosomes in a 46,XY/69,XXY case [36]. 69,XYY is possible only with diandry, because it requires two paternal Y chromosomes [4].

2.5. Genomic imprinting and placental phenotype

The correlation between origin and phenotype is the clearest human manifestation of genomic imprinting. With one maternal and two paternal sets, the placenta is large and hydatidiform and the fetus is small and malformed but proportionate; with two maternal sets and one paternal, the fetus has disproportionate growth restriction and the placenta is very small [49]. The double dosage of paternally expressed genes explains the trophoblastic hyperplasia, the high production of human chorionic gonadotrophin (hCG) and, through it, the hyperthyroidism, theca lutein cysts and risk of pre-eclampsia; molecular confirmation of origin therefore makes it possible to predict the spectrum of maternal complications and the risk of GTN [15, 20]. Immunohistochemistry for p57, the product of a maternally expressed imprinted gene, marks the presence of a maternal genome: it is negative in androgenetic complete mole and positive in PHM and in non-molar conceptions [23, 25]. Two paternal genomes are not sufficient, however, for molar development: only some PPM cases have a partial mole phenotype, and Joergensen and colleagues documented non-molar PPM triploidies [40, 43]. Oxford Desk Reference also mentions, as a speculative hypothesis, that trophoblastic disease might result from the combination of an abnormality of paternal genes with deletion of a maternal suppressor gene [4].

2.6. Mechanisms of diploid/triploid mixoploidy

The reference sources offer two explanations that are not mutually exclusive. In the first, put forward by Oxford Desk Reference in the context of postnatal mosaicism and syndactyly, mixoploidy arises from partial "rescue" of a triploid conception, with extrusion of the surplus pronucleus at the first cleavage and reincorporation at a subsequent division, so that the morula is a 3n/2n mosaic [21, 53]. In the second, described by Daniel and colleagues and cited by Oxford Desk Reference in the triploidy chapter, the starting point is a diploid zygote: delayed digyny, through incorporation of the second polar body pronucleus into a blastomere, or delayed dispermy, through incorporation of a second sperm pronucleus into a blastomere; a diploid gamete is excluded, because it would give rise to triploidy without a diploid line [4, 46]. In the same study, one apparent 3n/2n mosaic was a chimaera resulting from fusion of two zygotes, and in another the triploid line was confined to the placenta [46]. Van de Laar and colleagues, in 3 new cases with an extra maternal set and a review of 25 cases, and Brems and colleagues consider inclusion of the second polar body in an early diploid embryo the most likely mechanism [24, 54]. Daniel and colleagues (2001) described two digynic triploid/diploid mosaics, in one of which the diploid line had a postzygotic trisomy 16 absent from the triploid line [45].

In vitro fertilisation (IVF) embryology has added a third mechanism. In bovine embryos, haplotyping of 116 blastomeres from 23 embryos showed that the zygote can segregate entire parental genomes into distinct cell lineages as early as the first division ("heterogoneic division"), after both abnormal and normal fertilisation, generating chimaerism and mixoploidy [55]. Zhao and colleagues, with 118 bovine blastomeres, confirmed heterogoneic division in zygotes with multipolar and bipolar cleavage and showed that cells with whole-genome abnormalities activate stress responses leading to cell arrest or to blastocyst formation [56]. Carson and colleagues, in 8 cases of mixoploidy from Pittsburgh and a literature review, concluded that mixoploidy requires aberrant segregation of entire parental genomes in the first divisions and that most recognised cases are digynic, and described a digynic case involving two different sperm [57]. In 46,XX/69,XXY individuals, whose cell lines differ in chromosomal sex, genital ambiguity may occur [3].

2.7. Maternal genes and recurrent triploidy

In the vast majority of families, triploidy is an isolated event, but some families with recurrence point to a maternal predisposition to errors of meiosis or fertilisation. The variants described, normalised in VariantValidator against the MANE Select transcript (GRCh38), are listed in the table.

Other families support the existence of hereditary susceptibility without an identified gene. Brancati and colleagues described three consecutive triploid pregnancies in one woman, with maternal origin proven in two; Pergament and colleagues, two triploid conceptions (fetal death at 10 and 23 weeks) in a woman whose IVF embryos obtained by intracytoplasmic sperm injection (ICSI) were also triploid; Khawajkie and colleagues, a patient with four digynic triploid conceptions due to meiosis II failure, whose maternal cousin had a mature ovarian teratoma with the same mechanism [13, 59, 60]. Raymond and colleagues reported a monoandric digynic triploid miscarriage at 13 weeks in a 32-year-old woman with recurrent pregnancy loss, and Robinson and colleagues, molar and non-molar triploidy in successive pregnancies, in which molecular genetics and pathology distinguish the two situations for planning purposes [61, 62].

2.8. NLRP7 and KHDC3L: interface with recurrent hydatidiform mole

NLRP7 (HGNC:22947; 19q13.42) encodes an oocyte maternal-effect factor, a component of the cytoplasmic lattices and the subcortical maternal complex, required for establishment of maternal methylation at imprinted regions; it also restrains caspase-1-dependent IL-1β secretion and colocalises with KHDC3L [6]. The MANE Select transcript is NM_001127255.2; the GeneGuidance record uses NM_139176, without a version, which is not the MANE transcript [6, 8]. KHDC3L (HGNC:33699; 6q13; MANE NM_001017361.3) is required for global genomic methylation in the oocyte; biallelic variants cause imprinting defects that persist after fertilisation, and biparental diploid conceptuses develop as complete moles [7, 8]. In both cases inheritance is autosomal recessive with a maternal effect: the woman with biallelic variants is healthy and the disease is expressed in her pregnancies [6, 7]. The validity of the association of NLRP7 with recessive mole is classified as strong in GenCC (Labcorp/Invitae, PanelApp Australia) and as supportive in Orphanet; ClinGen has no curation [6]. The consensus of Slim and colleagues (2022) recognises variants in seven maternal-effect genes as a cause of recurrent mole, with NLRP7 as the principal gene and variants registered in the Infevers database [63].

The relationship with triploidy is limited. Moles in women with biallelic variants are characteristically biparental diploid (all of them, in a review of 123 molar tissues), but digynic triploid moles and mixed complete/partial features have been described in a patient with NLRP7 variants [6]. Fallahian and colleagues described two digynic triploid conceptions with classic complete mole histology and negative p57: one in a woman with a homozygous truncating NLRP7 duplication, and another in a woman who, like her sister, was compound heterozygous for KHDC3L (C6orf221) variants; the other pregnancies were biparental diploid [64]. In two patients with NLRP7 variants, 4 of 5 non-diploid products of conception were triploid, 2 due to fertilisation by more than one sperm, suggesting that some affected oocytes fail to block polyspermy [65]. By contrast, Manokhina and colleagues found only non-synonymous NLRP7 variants, without pathogenic mutations, in 17 women with recurrent miscarriage and an additional triploidy or complete mole, and found no association of these variants with primary recurrent miscarriage (n = 39), paternal triploid conceptions (n = 22) or partial moles, compared with 52 women who were fertile after age 37: NLRP7 and KHDC3L are not a common risk factor for triploidy [66]. The GeneReviews MEG-MLID chapter adds that maternal variants in NLRP7, KHDC3L, NLRP2, NLRP5 and PADI6 are also associated with multilocus imprinting disturbances in the offspring, mainly with a Beckwith-Wiedemann spectrum, and that the mother is the "molecular proband" [14]. A provisional phenotype, oocyte/zygote/embryo maturation arrest 25 (OMIM 621471, autosomal dominant), links a maternal heterozygous truncating NLRP7 variant to recurrent reproductive failure and multilocus imprinting disturbance [6].

2.9. Triploidy in embryos from medically assisted reproduction

Triploidy is common in cleavage-stage embryos [4]. In 1982 embryos with two pronuclei (2PN), ploidy was abnormal in 1% (0.8% triploid and 0.2% haploid); the proportion of triploids was 4.0% in 0PN, 6.5% in 1PN, 34.8% in 2.1PN and 74.1% in 3PN embryos, and time-lapse observation increased the ability to predict ploidy from 28.3% to 80.4% [67]. In a preimplantation genetic testing (PGT) programme in Hong Kong, triploidy was found in 0.8% (8/1049) and genome-wide uniparental disomy in 1.4% (15/1049) of blastocysts, both invisible to conventional read-count-based PGT for aneuploidy (PGT-A) [68]. In a retrospective series of 150 patients, 8.7% (44/508) of day 5 embryos were 3PN, with low blastocyst formation and pregnancy rates; the authors accept transfer of euploid 1PN/3PN blastocysts only in the absence of transferable 2PN embryos [69].

3. Clinical Spectrum and Manifestations by System

3.1. Natural history of triploid pregnancy

Triploidy affects about 1–2% of conceptions, and the vast majority are lost in the first trimester; some pregnancies reach the second trimester, and survival to the third is rare, ending in intrauterine or neonatal death [4, 15]. Selection is evident in the fall in frequency with gestational age: Lugthart and colleagues, citing earlier studies, report 0.03% of pregnancies at 10–12 weeks and 0.002% at 16–20 weeks, and that only about 1 in 10,000 triploid conceptions is born alive [19]. In EUROCAT (2000–2006), of the 296 cases registered after 20 weeks or diagnosed prenatally, only 10 (3%) were live born [12]. In modern prenatal series, without termination, the outcome is uniform: in Vienna (1999–2009), none of the 6 triploidies with a natural outcome was live born; in Amsterdam (2000–2018), of the 120 triploidies, 85 (70.8%) were terminated, 30 (25.0%) ended in fetal death, 5 had an unknown outcome and there were no live births or neonatal deaths; in Denmark (2008–2011), of the 25 cases detected by combined screening, 20 were terminated, 4 ended in miscarriage and 1 in stillbirth [19, 70, 71].

Gestational age at loss differs by origin. In Jacobs's Hawaiian series, mean gestational age was 122 days in paternal and 74 days in maternal triploids, but the difference reflects retention of the molar placenta rather than fetal survival [37]. Zaragoza and colleagues associated maternal cases with early embryonic death or, conversely, with relatively late death of a well-formed fetus [40]. The digynic type is the one most likely to survive into the second trimester, and in the Warsaw samples the diandric proportion fell from 64.3% between 11 and 14 weeks to 27.8% after 14 weeks [4, 44]. Fetuses with 2n/3n mosaicism may survive longer, and some reach term [4, 21].

3.2. Fetal and placental phenotype by parental origin

The two classic phenotypes are type I (diandric), with a well-grown fetus or moderate symmetrical FGR, a proportionate head or mild microcephaly and a large placenta with cystic changes, and type II (digynic), with severe asymmetrical FGR, relative macrocephaly and a small non-molar placenta [38, 45]. For the digynic type, Oxford Desk Reference adds possible holoprosencephaly, oligohydramnios and abnormal placental Doppler, and, for the diandric type, structural anomalies in 82% and raised maternal serum hCG in 80% [4]. The Smith text associates diandry with a well-grown fetus, but the legend of its Fig. 2 describes a 20-week 69,XXY fetus with severe FGR, myelomeningocele and 3–4 syndactyly as "consistent with two paternal copies and one maternal"; genotyped cohorts show that FGR occurs in 42.9% of diandric cases, always symmetrical, so the two descriptions are compatible [3, 19].

The Amsterdam cohort (two fetal medicine units, 2000–2018; 120 triploidies, 118 singleton and 2 twin; maternal age 31.6 ± 4.9 years; 71.6% detected before 18 weeks) determined the molecular origin in 46 cases, 32 maternal (69.6%) and 14 paternal (30.4%) [19].

The figure of 42.6% symmetrical FGR in the paternal cases is as published (6/14 corresponds to 42.9%). In the cohort as a whole, early FGR (crown-rump length, CRL, below the 5th centile at 10–12 weeks) occurred in 14/24 (58.3%), FGR by abdominal circumference below the 5th centile in 69/77 (89.6%) and overall FGR in 83/101 (82.1%), asymmetrical in 59/71 (83.1%); structural anomalies were present in 101/120 (84.1%), multiple (2 to 9) in 74 (61.6%), brain in 41.7%, limb in 40% and cardiac in 29.2% [19]. The limitations stated by the authors are the retrospective design, genotyping of only 46 cases, with wide confidence intervals, and serum markers in 12 of the 46 [19].

The Warsaw series (3 years; 9 diandric and 12 digynic cases with molecular origin, all referred for abnormal ultrasound) gives concordant results: FGR in 0/9 diandric and 11/12 digynic cases (all asymmetrical), structural defects in 8/9 and 10/12, multiple in 8/9 and 7/12, central nervous system anomalies in 5/9 and 5/12, cardiac in 6/9 and 6/12 (atrioventricular canal 1 and 1; tetralogy of Fallot 1 and 3), limb in 3/9 and 5/12 (polydactyly 3 and 5; clubfoot in 2 digynic cases), omphalocele in 4 and 1, increased NT in 6/9 and 0/12, increased nuchal fold in 3/9 and 0, and cystic placenta in 9/9 and 0/12 [20]. Gestational age at testing was 14.9 (11.7–17.6) weeks in diandric and 18.0 (12.4–26.3) weeks in digynic cases (p = 0.0391) [20].

On targeted transvaginal ultrasound at 12–16 weeks in Israel (2008–2014; 25 triploidies, about 1 in 5000 pregnancies), 4 had placental molar changes; in the remaining 21, asymmetrical FGR with abdominal circumference lagging two or more weeks behind head circumference was present in 21/21, oligohydramnios in 20/21, abnormal posterior fossa or dilated fourth ventricle in 20/21, absent gallbladder in 17/21, cardiac anomalies in 70%, renal anomalies in 55%, clenched hands in 55% and pulmonary hypoplasia in 67% [72]. The data of Joergensen and colleagues confirm the variability: frequent soft-tissue syndactyly and asymmetrical growth restriction, varied fetal phenotypes at autopsy in both types and some nearly normal fetuses [4, 43].

3.3. Anomalies by system in complete triploidy

Smith lists the anomalies present in at least half of cases: a large placenta with a tendency to hydatidiform change; disproportionate prenatal growth deficiency, affecting the skeleton more than the head; dysplastic calvaria with a large posterior fontanelle, hypertelorism with ocular defects (from colobomas to microphthalmia), low nasal bridge, low-set malformed ears and micrognathia; syndactyly of fingers 3 and 4, single palmar crease and talipes equinovarus; atrial and ventricular septal defects; in male fetuses, hypospadias, micropenis, cryptorchidism and Leydig cell hyperplasia; brain anomalies such as hydrocephalus and holoprosencephaly; adrenal hypoplasia; and renal anomalies, including cystic dysplasia and hydronephrosis [3]. With a frequency below 50%: aberrant cranial shape, choanal atresia, cleft lip or palate, iris heterochromia, cutaneous pigmentary dysplasia, myelomeningocele, macroglossia, omphalocele or umbilical hernia, biliary tract anomalies (including gallbladder aplasia), incomplete rotation of the colon, proximally placed thumb, fifth finger clinodactyly and widely spaced toes [3]. The Orphanet definition summarises the picture as early FGR with neural tube defects, facial anomalies, cleft lip or palate, congenital heart disease, genital malformations and peripheral skeletal anomalies [1].

At autopsy of 43 complete triploids and 11 mosaics born at 22 weeks or later, Doshi and colleagues described Leydig cell hyperplasia, increased haematopoiesis and ovarian, adrenal and pulmonary hypoplasia, with partial mole in about 70% of placentas and a spectrum ranging from nearly normal to multisystem involvement [73]. In the Sydney series, 5 of 6 69,XXY fetuses had hypoplastic or ambiguous external genitalia (2 registered as phenotypically female), and all diandric fetuses had testicular gonads; in the only digynic 69,XXY fetus, sex reversal was complete, with a normal uterus and fallopian tubes and histologically ovarian gonads [45]. The Portuguese case of Fontoura Oliveira and colleagues also documents female external genitalia in a presumably digynic 69,XXY fetus [74].

3.4. Placenta and partial hydatidiform mole

PHM has identifiable embryonic or fetal tissue, villi of variable size with focal oedema, cavitation (cisterns) and trophoblastic hyperplasia [4, 25]. Between 90% and 93% of PHMs have a triploid karyotype of paternal origin [4]. The clinical presentation of PHM includes vaginal bleeding, frequent nausea and vomiting, hyperemesis gravidarum, hyperthyroidism and risk of spontaneous miscarriage [2]. With early ultrasound diagnosis, hyperemesis, pre-eclampsia and hyperthyroidism have become less frequent in molar pregnancies, and the RCOG lists hyperemesis, uterine enlargement, hyperthyroidism, early-onset pre-eclampsia and abdominal distension from theca lutein cysts as less common presentations [23, 25]. In digynic cases, the placenta is small, thin and without cystic changes; in the Portuguese case, both placentas had low or very low weight, with no macroscopic changes, one of them with severe chronic intervillositis [19, 74].

3.5. Maternal complications

Maternal complications are concentrated in diandric triploidy and track trophoblastic mass and hCG. In the Warsaw series, with molecularly confirmed cases beyond 13 weeks, the comparison was as follows [20].

There was no proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), transaminases rose slightly in 2 diandric cases and hyperthyroidism was unrelated to the hCG level [20]. The authors attribute the lower severity relative to the literature to earlier diagnosis through first-trimester screening (NT above 3.5 mm in 66.7% of diandric cases and markedly raised free β-hCG in all with data) and reviewed 43 published cases of hypertension or pre-eclampsia in apparently diandric triploidy, with mean onset at 19 weeks (14–39) and severe complications such as eclampsia, HELLP, cardiomyopathy, pulmonary oedema and severe ovarian hyperstimulation syndrome (OHSS) [20]. The incidence of hypertension or pre-eclampsia in triploidy is estimated at 4.3% to 35%, and Jauniaux and colleagues, cited in the same review, reported theca lutein cysts in 8.6% and hyperemesis in 5.7% of diandric and digynic triploidies; only 73% of molecularly confirmed diandric cases in the literature had a molar appearance [20, 75]. In Iowa and North Carolina (1987–1996), 6 of 17 second-trimester triploidies (35%) had pre-eclampsia or hypertension, with onset between 15 and 22.5 weeks, all with extremely high hCG and placentomegaly; among the 7 without pre-eclampsia who had serum screening, hCG was below 0.09 MoM in 5 [75]. In the Amsterdam cohort, maternal complications occurred in 26/120 (21.6%): vaginal bleeding in 24 (20%), mostly before 18 weeks and with a normal placenta in 16 of the 24, hypertension in 1 without molar changes and pre-eclampsia in 1, with a hydropic and cystic placenta, markedly raised β-hCG at 20 weeks and confirmed partial mole [19]. Bleeding predominated in digynic cases (50% in Warsaw), which shows that the absence of a mole does not eliminate all maternal morbidity [20].

Case reports illustrate the potential severity. A 36-year-old multiparous woman with a spontaneous conception had severe hypertension with proteinuria at 18 weeks, a large multicystic placenta, fetal anomalies, hyperreactio luteinalis and an sFlt-1/PlGF ratio (soluble fms-like tyrosine kinase-1 / placental growth factor) of 270, with rapid resolution after medical termination at 19 weeks [76]. A 32-year-old woman with spontaneous triploidy and a non-molar placenta had early-onset pre-eclampsia and HELLP, with termination of pregnancy for medical reasons in the second trimester and OHSS four weeks later, managed conservatively [77]. In a dichorionic twin pregnancy with one triploid twin and chronic hypertension, signs of pre-eclampsia at 18 weeks led to selective reduction of the affected twin, with delivery of a healthy newborn at 37 weeks; in another twin pregnancy, the partial molar placenta continued to grow after death of the triploid fetus and contributed to pre-eclampsia [78, 79]. A 69,XXY/46,XX mosaic was associated with severe early-onset pre-eclampsia, with a live-born infant with musculoskeletal anomalies [80].

Mirror syndrome (Ballantyne syndrome), defined by maternal oedema associated with fetal or placental hydrops, shares features with pre-eclampsia and has been described with fetal and placental malformations or tumours. In a systematic review of 56 cases (PubMed up to December 2008), the causes were Rh isoimmunisation (29%), twin-twin transfusion syndrome (18%), viral infection (16%) and fetal or placental malformations or tumours (37.5%); diagnosis was made between 22.5 and 27.8 weeks, with oedema in 80–100%, hypertension in 57–78% and proteinuria in 20–56%, intrauterine death in 56%, severe maternal complications in 21.4% and resolution 4.8 to 13.5 days after delivery [81]. In a review of 113 cases, fetal or neonatal mortality was 67.26% [82]. The systematic review by Biswas and colleagues showed heterogeneous criteria, haemodilution in all studies that assessed it, major maternal complications in 89.4% (postpartum haemorrhage 44.7%, transfusion 19.1%, intensive care 12.8%, heart failure 10.6%, pulmonary oedema 8.5%) and survival of 7.7% in continued pregnancies [83]. In one case of Ballantyne syndrome, laboratory evaluation found BNP 523 pg/mL, sFlt-1 15,600 pg/mL, hCG 404,000 IU/L and aldosterone 2070 pg/mL [84]. The reviews do not report triploidy separately, so the frequency of mirror syndrome in triploidy is not known from the sources consulted.

3.6. Postnatal survival in complete triploidy

Birth after 28 weeks is uncommon and is accompanied by severe FGR; Smith states that all cases of complete triploidy were stillborn or died in the early neonatal period, with a maximum recorded survival of 5 months [3]. The case literature describes longer survival, always with death in the first year.

The Unique guide, based on the literature up to 2005, describes the 10.5-month survivor as a child who went home, smiled and seemed to recognise the parents and sibling, and who died after a seizure; it also states that four of five newborns who lived longer than a month were digynic [30]. The discrepancy between Smith's maximum of 5 months and the published 10.5 months is resolved in favour of the primary source [18].

3.7. Diploid/triploid mixoploidy

Diploid/triploid mixoploidy is less frequent than complete triploidy. The diagnostic features are asymmetrical growth deficiency, mild syndactyly and, occasionally, genital ambiguity in 46,XX/69,XXY individuals; patients usually survive, with some degree of psychomotor delay, learning disabilities, seizures, short stature, truncal obesity, syndactyly, scoliosis and asymmetry, and some resemble Silver-Russell syndrome [3]. Syndactyly mainly affects fingers 3–4 and toes 2–3, with bulbous toe tips and clinodactyly; the skin shows streaks of hyper- or hypopigmentation, and Oxford Desk Reference states that the phenotype usually includes significant intellectual disability [21, 53]. The degree of skeletal asymmetry does not correspond to the proportion of triploid cells [3, 36].

The review of 25 cases by van de Laar and colleagues summarises the phenotype as intellectual disability, truncal obesity, body or facial asymmetry, growth delay, hypotonia, micropenis, low-set malformed ears and micrognathia [24]. Rittinger and colleagues described severe early growth delay with later truncal obesity, hypotonia, clinodactyly, syndactyly, asymmetry and pigmentary anomalies, frequently late diagnosis and overlap with imprinting syndromes, in the case of a 14-year-old girl with moderate disability [89]. Natera-de Benito and colleagues highlighted, in 3 46,XX/69,XXX cases, pigmentation along the lines of Blaschko and anomalies of other ectodermal tissues as the main signs, with intellectual disability, truncal obesity, short stature, hemihypertrophy and small, narrow hands with clinodactyly and camptodactyly [90]. Dental lines of Blaschko, pigmentary mosaicism and an association with hypomelanosis of Ito have been described, and the adult phenotype was described by Jewell and colleagues [91–94]. A case reported by Lalani and colleagues (a girl delivered by caesarean section at 32 weeks for growth arrest) had gastro-oesophageal reflux, laryngomalacia, decreased intestinal motility, hypotonia and motor and cognitive delay; the lymphocyte karyotype was 46,XX, and a skin biopsy at age 2 years showed a 68,XX line; at 6.4 years, height was below the 3rd centile, weight at the 42nd centile and head circumference above the 97th centile, with low-set ears, depigmented areas of the iris and hair, ptosis, strabismus, hypoplastic teeth, pectus excavatum, scoliosis and 3–4 finger and 2–3 toe syndactyly [95].

The prognosis is not uniformly favourable. In the series of Carson and colleagues, only 1 of 8 cases of mixoploidy resulted in a healthy live birth, and the others ended in miscarriage, termination, or fetal or neonatal death [57]. Boonen and colleagues ask whether mixoploidy is rare or underdiagnosed, given the need to study non-haematological tissues [96]. The comparison with diploid-tetraploid mixoploidy and the delineation of the syndrome by Tharapel and colleagues and by Carakushansky and colleagues complete the reference literature [35, 97, 98].

4. Clinical Recognition and Red Flags

4.1. When to suspect in the first trimester

Triploidy should be considered when first-trimester combined screening shows an extreme biochemical pattern, because this is the setting in which most viable cases are now detected. In Denmark (2008–2011; 198,427 singleton pregnancies screened between 11+2 and 14+0 weeks), combined screening for trisomies 21, 18 and 13 detected 25 of 30 triploid fetuses (83.3%): 23 because of a high-risk result and 2 because of structural anomalies; CRL was smaller than expected from the date of the last menstrual period in 95%, and biparietal diameter was larger than expected in 8 [71]. The guiding signs are: markedly raised free β-hCG with increased NT and a bulky or cystic placenta (diandric pattern); very low PAPP-A and free β-hCG with normal NT and an embryo small for gestational age, with a disproportionately small trunk (digynic pattern) [19, 30, 99]. A discrepancy between CRL and dating, when it leads to redating of the pregnancy, can mask early FGR, as the Unique guide notes for the diandric form [30, 71].

4.2. When to suspect in the second and third trimesters

In the second trimester, the combination of early asymmetrical FGR with abdominal circumference lagging behind head circumference, oligohydramnios, posterior fossa anomalies, absent gallbladder, 3–4 syndactyly and a small placenta suggests digynic triploidy; a large cystic placenta with a normally growing fetus or symmetrical FGR suggests diandric triploidy or partial mole [19, 20, 72]. Oxford Desk Reference recommends considering triploidy in fetuses with marked FGR and syndactyly, in neural tube defects with severe FGR, in holoprosencephaly, in short limbs with assessment of the placenta, in radial ray defects and in non-immune fetal hydrops, in which chromosomal causes, including triploidy, account for 13.4% of 5437 cases [53, 100–105]. In fetal or neonatal death with a radial ray defect, the diagnoses to exclude are triploidy, trisomy 18 and Cornelia de Lange syndrome [104]. The digits can be visualised on ultrasound from the second trimester [53]. On second-trimester serum screening, the two patterns are raised alpha-fetoprotein (AFP) and hCG with low or normal oestriol, and low or normal AFP with low hCG and oestriol [30].

4.3. When to suspect after birth or in childhood

Complete triploidy in a live-born infant presents with severe FGR, relative macrocephaly with a small face, 3–4 syndactyly and multiple anomalies [3]. Diploid/triploid mixoploidy should be considered in a dysmorphic child with streaky pigmentation following the lines of Blaschko, body asymmetry, 3–4 finger syndactyly with 2–3 toe syndactyly and bulbous digit tips; in these situations, Oxford Desk Reference recommends a skin biopsy for karyotyping [53, 106]. A Silver-Russell-like phenotype with syndactyly, fetal akinesia with suspected mosaicism, and truncal obesity with intellectual disability and asymmetry should also prompt consideration of the diagnosis [3, 24, 107].

4.4. Maternal red flags and emergency signs

4.5. Newborn screening

There is no newborn screening for triploidy or mixoploidy. The diagnosis of the complete form is almost always prenatal (92% of EUROCAT cases) or made on the products of conception [12].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Diagnostic criteria

There are no formal clinical criteria. The diagnosis of triploidy is cytogenetic or molecular (69 chromosomes, or a triploid allelic pattern at all informative markers), and that of mixoploidy requires demonstration of 46 and 69 cell lines in the same individual [1, 24]. The diagnosis of partial mole is histological, and ploidy alone is not sufficient: the RCOG requires histological confirmation of complete mole, partial mole, atypical placental site nodule, and placental site and epithelioid trophoblastic tumours, and notes that not all triploid pregnancies are partial moles [25]. The diagnosis of GTN, by contrast, does not require histological confirmation and is based on the course of hCG [23, 25].

5.2. Biochemical and ultrasound screening

The table summarises the patterns described by origin. The median values come from small samples and serve to guide suspicion, not to classify an individual case.

In the Israeli series of 12,322 combined screens between 10 and 14 weeks, the 8 triploidies (at least 1 in 1540) showed both patterns: type I with extremely elevated free β-hCG and increased NT, and type II with very low PAPP-A and free β-hCG and normal NT [99]. Lugthart and colleagues recommend that maternal serum hCG also be obtained and expressed in MoM in the second trimester, to integrate the findings [19]. Ultrasound prospectively predicted the origin in 30 of the 46 genotyped cases from Amsterdam, all correctly, using simple criteria: asymmetrical FGR indicates maternal origin and molar changes indicate paternal origin, requiring the presence of one or more criteria for one origin and the absence of those for the other [19]. Massalska and colleagues, in an earlier series of 67 cases without genotyping, were unable to establish the origin by ultrasound in about 20% [19]. In Denmark, suspicion of mole on ultrasound, gross examination, or histology, or an elevated hCG, predicted PPM origin with very high specificity but with sensitivity below 100% [43].

Ultrasound has low sensitivity for isolated PHM. According to the RCOG, the classic criteria (enlarged placenta or cystic changes in the decidual reaction with an empty sac or missed miscarriage) have a sensitivity of 95% for complete mole and 20% for partial mole, with positive predictive values of 40% and 22%; with additional criteria (placental cystic spaces and a ratio of transverse to anteroposterior sac diameter greater than 1:1.5), 41.4% of PHMs are correctly diagnosed before evacuation, compared with 86.4% of complete moles, and in one early pregnancy unit ultrasound identified 88.2% of complete and 56% of partial moles [25]. Before evacuation, only 35–40% of moles are correctly identified before 14 weeks and about 60% thereafter [25]. In Amsterdam, ultrasound suspicion of partial mole (22 cases, 18.3%; median 13.1 weeks) was confirmed histologically in 9 of the 12 with histology (75%), inconclusive in 2, and not confirmed in 1 [19].

5.3. Cell-free DNA (cfDNA) screening

Counting methods based on massively parallel (shotgun) sequencing compare the relative representation of chromosomes and do not detect triploidy, because all autosomes are equally increased; one case of failure of a counting test has been published [19, 109]. Single-nucleotide polymorphism (SNP)–based methods, with parental genotypes, can detect triploidy: in diandric triploidy, through the presence of multiple paternal haplotypes; in digynic triploidy, indirectly, through a very low fetal fraction [19, 110]. In an 11–13-week series with 4 diandric, 4 digynic, and 48 euploid pregnancies, the diandric cases showed multiple paternal haplotypes, the digynic cases a corrected fetal fraction below the 0.5th percentile, and a result was obtained in 44 of the 48 euploid pregnancies (91.7%) [110]. Fleischer and colleagues described the utility and difficulties of testing in digynic triploidy [111].

In the series of Kantor and colleagues, the other explanations for the extra haplotype were confirmed (460; 59.5%) or suspected (39; 5.0%) vanishing twin, pregnancy loss (75; 9.7%), normal singleton pregnancy (77; 10.0%), viable twins (23; 3.0%), and other causes (15; 1.9%: 3 complete moles, 2 chimeras, 3 maternal kidney transplants, 3 twins from donated oocytes, 1 maternal melanoma, 1 triplet pregnancy reduced to twins, 1 translocation); median fetal fraction did not differ between digynic (8.0%) and diandric (11.9%; p = 0.30) cases [112]. Triploidy was confirmed or suspected in 1 in 4722 tested (0.021%), with an estimated 1 in 5543 for diandric and 1 in 31,874 for digynic triploidy, which is underdetected because of the low fetal fraction [112]. The management proposed by the authors for an extra haplotype is ultrasound (viability, twins, signs of triploidy), review of any history of transplantation, oocyte donation, or cancer, serum markers, and definitive diagnosis by invasive testing [112–115]. A series of 3 dichorionic twin pregnancies with complete mole and a normal fetus showed that SNP-based cfDNA identifies the androgenetic origin of the genome [116]. A case of live-born triploidy after amniocentesis was declined illustrates that cfDNA does not replace diagnostic testing [87].

Current guidelines address triploidy only indirectly. The ACMG (2023) strongly recommends non-invasive prenatal screening (NIPS) over traditional methods for trisomies 21, 18, and 13 in singleton and twin pregnancies and that it be offered for sex chromosome aneuploidies; it suggests, as a conditional recommendation, offering screening for 22q11.2 deletion; it does not mention triploidy; and it describes "no-call" results in about 1% of samples, mainly due to insufficient fetal fraction, with a result in 75–80% of repeat tests, noting that ACOG and SMFM recommend offering diagnostic testing after a no-call result [117]. The Society for Maternal-Fetal Medicine (SMFM), in Consult Series #74 (2025), adopted by the American College of Obstetricians and Gynecologists (ACOG) in its January 2026 Practice Advisory, which replaces the 2020 Practice Bulletin 226 [118], recommends that cfDNA for trisomies 21, 18, and 13 be available to all pregnant patients (GRADE 1B), does not recommend population screening for microdeletions or routine use for large genomic deletions or duplications (GRADE 1C), and specifies that a positive result be followed by genetic counselling, detailed ultrasound, and a recommendation for diagnostic testing by chorionic villus sampling (CVS) or amniocentesis, and that a non-reportable result lead to an offer of counselling, comprehensive ultrasound, and diagnostic testing, given the increased risk of aneuploidy [119, 120]. The same document retains first- and second-trimester serum screening when cfDNA cannot be offered, for example with a vanishing twin, maternal transplantation, or maternal mosaicism, and notes that serum screening can detect placental abnormalities not detected by cfDNA [120]. There is therefore a divergence between the ACMG and SMFM/ACOG regarding 22q11.2 deletion, with no direct consequence for triploidy; in none of the guidelines reviewed is triploidy a stated target of screening.

5.4. Diagnostic tests and determination of parental origin

Oxford Desk Reference notes that QF-PCR and MLPA detect copy-number changes in products of conception, that triploidy is not detected by aCGH alone and, citing the meta-analysis by Dhillon and colleagues, that microarray and karyotype are concordant in 86.0% (95% CI 77.0–96.0), that microarray detects 13% (95% CI 8.0–21.0) additional anomalies and karyotype 3% (95% CI 1.0–10.0), mainly balanced translocations, with variants of uncertain significance in 2% (95% CI 1.0–10.0) [16]. In the BCNatal (Barcelona) series, 46 triploidies diagnosed by QF-PCR on villi or amniotic fluid, with maternal saliva (13 ongoing pregnancies and 33 miscarriages), included 26 diandric cases (56%); pathology agreed with partial mole in 14 (54%), was normal in 6 (23%), and was not possible in 6 (23%, miscarriages managed medically), so the authors consider QF-PCR more accurate than pathology [121]. In 10,000 consecutive pregnancy losses genotyped by QF-PCR in Moscow (2018–2024), the criteria for triploidy were peak ratios of about 2:1 or 1:1:1 at non-homozygous markers [17].

5.5. Histology, p57, and genotyping of the products of conception

The RCOG recommends histological examination of all products of conception from miscarriages without identified fetal parts and, when there is no histology, a urine pregnancy test three weeks after the miscarriage [25]. The Danish guideline calls for one fixed sample for histology and one unfixed sample for genetic study [124]. p57 immunostaining is highly specific for complete mole (negative) but does not distinguish PHM from non-molar miscarriage; STR genotyping identifies the absence of a maternal contribution (complete mole) and diandric triploidy (partial mole) [23, 125]. The Brazilian scoping review by Teixeira and colleagues (9 studies, 2015–2025) adds that divergent p57 expression, which is rare, requires molecular methods [125]. In NLRP7-associated moles, p57 may be discordant [6].

Morphology alone fails in a substantial proportion of PHMs. In 20 diandric and 22 digynic cases, cisterns had a PPV of 93%, specificity of 96%, and sensitivity of 70%; cisterns combined with villi of 2.5 mm or more, trophoblastic hyperplasia, or syncytiotrophoblastic lacunae had a specificity and PPV of 100%, with a sensitivity of 60–65%; interobserver agreement was moderate (kappa 0.57), and histology failed to classify 35–40% of PHMs [126]. Among 20 specimens with known fetal triploidy, 13 (65%) were PHMs by genotyping; 4 of these had initially been interpreted as normal or non-molar, and only 3 (23%) had villi of 2.5 mm or more with cisterns, leading the authors to propose reflex genotyping of all specimens with known fetal triploidy [127]. In Slovakia, of 68 suspected PHMs genotyped by QF-PCR, 35 (51%) were diploid and 33 (49%) partial moles (31 diandric triploid and 2 triandric tetraploid), with no digynic triploidy, suggesting that ploidy by FISH, cytometry, or karyotype may suffice where genotyping is not available [128]. In the absence of genotyping, FIGO accepts hCG surveillance of women with suspected PHM based on atypical or dysmorphic villous morphology [23].

Genotyping of molar tissue against parental DNA is also the key test for recurrent mole: a biparental diploid mole warrants testing NLRP7 and KHDC3L in the woman, whereas androgenetic or triploid moles argue against this cause [6]. In research settings, circulating gestational trophoblasts isolated from maternal blood in 15 suspected moles (6–13 weeks) were obtained in 87% beyond 10 weeks and diagnosed 2 androgenetic moles, 3 diandric triploid moles, and 6 biparental diploid conceptions [129].

5.6. Diagnosis of diploid/triploid mixoploidy

The diagnosis of mixoploidy depends on the tissue. In about 75% of cases the blood karyotype is normal and the diagnosis can be made only in cultured fibroblasts [24]. The triploid line may disappear from leucocytes, lymphocytes may lack triploid cells, proportions vary between fibroblasts from different limbs, and the triploid line is lost with prolonged culture [3, 36]. Triploid cells can be found in urinary sediment or buccal smears, and prenatal confirmation has been achieved in fetal urine cells [89, 130]. Failure of prenatal diagnosis by amniocentesis has been described [131]. Natera-de Benito and colleagues diagnosed their cases in fibroblasts from hypopigmented skin [90]. In the case reported by Mahon and colleagues, amniocentesis at 20 weeks showed 69,XXX in 6/30 cells (20%) and 46,XX in 24/30, with QF-PCR suggesting digynic origin; after birth, blood karyotype and microarray were normal, and FISH with centromeric probes for chromosomes 8 and 9 on a buccal smear showed three copies in 38 of 100 cells [122]. The authors recommend alternative tissues (buccal mucosa, skin, urine) when blood is normal and consider amniocentesis the best prenatal tissue, with postnatal confirmation [122].

Oxford Desk Reference quantifies the limit of conventional analysis: 30 cells analysed without mosaicism exclude 10% mosaicism with 95% confidence; if suspicion persists despite normal microarray and lymphocyte karyotype, another tissue lineage should be analysed (fibroblasts, skin biopsy, saliva) [21]. Genome sequencing can detect mixoploidy through programmatic analysis of allele frequencies, according to a non-peer-reviewed preprint from the Undiagnosed Diseases Network [132].

5.7. Practical algorithm

The algorithm is derived from the recommendations of the RCOG, FIGO, and Oxford Desk Reference and from the series cited [19, 21, 23, 25, 112, 127]. Oxford Desk Reference considers parental karyotyping not indicated after a triploidy [4].

5.8. Report content

The report of a triploidy should state the tissue analysed and the method, the chromosome formula (69,XXX, 69,XXY, or 69,XYY; or, in mosaicism, both lines with the number of cells in each, e.g. mos 69,XXX[6]/46,XX[24] in the case of Mahon and colleagues), the parental origin when determined (dispermic diandric; digynic, specifying meiosis I or II), and the limitations of the method (low-level mosaicism not excluded; aCGH does not detect triploidy). When maternal genes are studied, the report states the gene, the versioned MANE transcript (NLRP7 NM_001127255.2; KHDC3L NM_001017361.3), the variant in HGVS nomenclature, the zygosity, and the classification according to ACMG/AMP criteria; the CCNB3, HORMAD2, and PLCD4 variants described in recurrent triploidy are each supported by evidence from a single family and do not, on their own, support a diagnosis [8–10, 58, 63]. There is no reliable prenatal test for the multilocus imprinting disturbances associated with maternal variants, and prenatal sequencing for the maternal variants is not indicated, because the fetus is heterozygous [14].

6. Differential Diagnosis

6.1. Comparison table

6.2. Main differentials

The first differential is obstetric and trophoblastic: with a cystic placenta, the task is to distinguish diandric triploidy with partial mole, complete mole with a normal co-twin, placental mesenchymal dysplasia, and non-molar villous lesion. The distinction has consequences: in complete mole with a co-twin, early fetal loss is about 40%, preterm birth about 36%, and pre-eclampsia up to 20% (4% in a large British series), with no increase in GTN according to the RCOG, and 51% surviving babies and chemotherapy in 15% in 153 additional cases; FIGO reports 40–60% live births and GTN in 27–46%, compared with 15–20% in singleton complete moles [23, 25]. The RCOG therefore recommends considering invasive testing for fetal karyotype when it is unclear whether the pregnancy is a complete mole with a normal co-twin or a singleton PHM, and when mesenchymal dysplasia is suspected [25]. SNP-based cfDNA offers a non-invasive route: in the series of Benn and colleagues, most results with apparent genome-wide paternal uniparental disomy corresponded to complete mole with a coexisting fetus, all with isodisomy, no Y chromosome in the uniparental line, fetal fraction of 2% or less in 28, and molar fraction of 10–58% [115]. Sahebdel and colleagues described a bipartite placenta with a triploid hydropic portion and a diploid fetus [133]. Double trisomy 16 and 22 can clinically mimic PHM [134].

The second differential is familial recurrent mole. When a woman has repeated moles, tissue genotyping separates sporadic androgenetic and diandric triploid moles from biparental diploid moles, which point to NLRP7 or KHDC3L [6]. A digynic triploid conception with a complete mole phenotype and negative p57 is unusual and should raise the possibility of familial biparental mole [64]. A non-molar digynic triploidy, by contrast, does not indicate trophoblastic risk [23].

The third differential is fetal. The main diagnoses for FGR with multiple anomalies are trisomies 18 and 13 and triploidy; the placenta (large and cystic or small) and head–abdomen asymmetry help to guide the diagnosis, and QF-PCR rapidly resolves the question [101, 103, 104]. Trisomies 18 and 13 and the approach to the fetus or newborn with multiple anomalies are part of the differential diagnosis. In non-immune fetal hydrops, triploidy is among the chromosomal causes (13.4% of 5437 cases, without breakdown) [105].

The fourth differential is postnatal and concerns mixoploidy. Silver-Russell syndrome shares FGR with relative macrocephaly and asymmetry, and some patients with mixoploidy resemble it; 3–4 syndactyly, streaky pigmentation, truncal obesity and intellectual disability point to mixoploidy and require fibroblast studies [3, 36, 89]. Hypomelanosis of Ito is a phenotypic description of pigmentary mosaicism that may correspond to diploid/triploid mixoploidy [21, 93]. Confined placental mosaicism includes that of triploid lines [46].

7. Treatment and Risk Management Strategies

7.1. General principles

There is no treatment for triploidy or for diploid/triploid mixoploidy. Management has three components: the obstetric decision after prenatal diagnosis, protection of maternal health (hypertensive, endocrine, and trophoblastic complications) and, in mixoploidy, developmental and growth follow-up. The drugs mentioned are intended for maternal complications or for GTN, not for the fetus or child [23, 25].

7.2. Counselling and decision-making after prenatal diagnosis

Once complete triploidy is confirmed, counselling conveys that there are no reports of prolonged survival: live-born infants die in the first year, with a published maximum of 10.5 months, and prenatal series without termination have no live births [18, 19, 70]. Most families choose termination (70.8% in Amsterdam; 80% of cases detected by Danish screening) [19, 71]. The factors to weigh include maternal risk: the likelihood of pre-eclampsia in diandric triploidy with a molar placenta is an explicit clinical argument in the decision, according to the Unique guide, and maternal complications occurred in 88.9% of diandric cases in the Warsaw series [20, 30]. Knowing the diagnosis allows the pregnant woman to choose termination or to decline a caesarean delivery for fetal indication in a lethal diagnosis; Bautista and colleagues describe a caesarean delivery at 37 weeks for a non-reassuring tracing in a woman who had declined amniocentesis, with neonatal death on day 20 [87]. Communication with the family shapes the experience: Mangarov and colleagues report how a reassuring second opinion created expectations that were not borne out [88]. The Unique guide recommends access to a genetics consultation and to psychological and patient-organisation support, whatever the decision [30].

7.3. Termination, evacuation, and management of the products of conception

The recommendations in the table come from the RCOG, FIGO, and the Danish guideline [23, 25, 124]. The Unique guide describes, for British practice in 2005, dilation and curettage or suction under general anaesthesia before 14 weeks and prostaglandin induction after 14 weeks [30]. The guidelines consulted do not state the dose of anti-D immunoglobulin; the label includes hydatidiform mole and miscarriage among the pregnancy complications for which prophylaxis is indicated and recommends a single dose of 300 µg (1500 IU) intravenously or intramuscularly, as soon as possible and within 72 hours (Portuguese SmPC for Rhophylac® and the FDA label for the same product), with an additional dose if feto-maternal haemorrhage exceeds that neutralised by this dose [137, 138]. National protocols that use lower doses for first-trimester termination diverge from this label.

7.4. Continuation of pregnancy

When the pregnant woman chooses to continue the pregnancy, or the diagnosis is made late, surveillance focuses on blood pressure and proteinuria, and the Unique guide states that, if pre-eclampsia develops, delivery is induced [30]. Case series and reports suggest that thyroid function, the ovaries and, in selected cases, the sFlt-1/PlGF ratio be considered, but no guideline defines intervals [20, 76]. In mirror syndrome with non-immune hydrops, the SMFM (Consult Series #75, 2026, which replaces Guideline #7) recommends individualised counselling on delivery or termination, with expectant management only in rare circumstances and after counselling on the maternal risks (GRADE 1C); fetal diagnostic testing with chromosomal microarray (CMA), with or without karyotype, when one or more fetal effusions are present (GRADE 1C); exome or genome sequencing if CMA and karyotype are not diagnostic (GRADE 1C); preterm delivery reserved for obstetric indications, including pre-eclampsia or mirror syndrome (GRADE 1C); corticosteroids if delivery is anticipated within the next 7 days and resuscitation is desired; and caesarean delivery for the usual obstetric indications when there is a neonatal care plan (GRADE 1C) [108]. Better fetal survival in mirror syndrome from other causes was associated with in utero correction of the hydrops or anaemia, which does not apply to triploidy [82].

In twin pregnancies with one triploid fetus, selective reduction of the affected twin was used in a dichorionic pregnancy with pre-eclampsia at 18 weeks, with delivery of a healthy newborn at 37 weeks; however, the molar placenta may continue to grow after death of the triploid fetus and sustain the pre-eclampsia [78, 79]. The RCOG recommends referring twin pregnancies with a viable fetus and a mole to a regional fetal medicine centre and a GTD centre and counselling on perinatal morbidity and GTN risk (D) [25].

7.5. Specific maternal complications

Symptomatic hyperthyroidism (33.3% of diandric cases in Warsaw), hyperemesis (44.4%), and theca lutein cysts (44.4%) resolve with uterine evacuation and the fall in hCG [20]. OHSS may develop weeks after termination: in the case of Wali and colleagues, four weeks later, with conservative management; the authors warn of the risk of unnecessary surgery and recommend monitoring the ovaries after a triploidy with hyperstimulation [77]. The sources consulted do not provide pharmacological regimens specific to triploidy for pre-eclampsia or hyperthyroidism, which follow general obstetric standards.

7.6. Gestational trophoblastic neoplasia after partial mole

Post-molar GTN is diagnosed by the FIGO criteria: an hCG plateau over four measurements during at least 3 weeks (days 1, 7, 14, and 21); a rise over three consecutive weekly measurements during at least 2 weeks (days 1, 7, and 14); or histological choriocarcinoma [23]. The Danish guideline defines persistent disease as stagnation (decline of less than 10% over three measurements), a rise, or detectable hCG after 6 months, with chest radiography, ultrasound, and referral to oncology (A) [124]. In a reference centre series of 111 PHMs (1995–2010), 35 women developed GTN, with a median of 47 days (25–119) to diagnosis and a median hCG of 475 mIU/mL (20–52,630); all had stage I, low-risk disease, all achieved remission, and 85.7% received first-line methotrexate; GTN was more frequent when the PHM was the first pregnancy event (37.1% vs 17.1%; p = 0.03) [139]. The proportion of 35/111 reflects referral-centre recruitment and not the population rate.

Low-risk GTN (FIGO score of 6 or less) is treated with a single agent; the recommended doses are those of the FIGO 2025 first-line regimens, shown in the table; the labels are given in the last column for comparison, and some FIGO regimens fall outside the labelled conditions [23, 140, 141]. The regimens are intended for women with low-risk GTN; the FDA methotrexate label indicates it in adults with GTN and the dactinomycin label in post-menarchal patients. FIGO sets a maximum only for the 5-day methotrexate regimen (25 mg per dose); for the other regimens, no maximum dose is defined by FIGO or by the labels consulted for GTN [23, 140, 141].

The 2016 Cochrane review and a 2021 meta-analysis, cited by FIGO, suggest greater efficacy of actinomycin D, with complete remission in 80.2% versus 65.1% with methotrexate (odds ratio 2.15; 95% CI 1.70–2.73), but they included studies with inferior methotrexate regimens [23]. About 30% of low-risk patients develop resistance to the single agent; primary resistance is defined as a rise or plateau of β-hCG (decline of less than 10%) over the first two cycles, and secondary resistance as a plateau or rise after an initial response; switching from methotrexate to actinomycin D achieves a response in 76–87%, especially with relatively low hCG, and second-line avelumab had a complete response rate of only 53%, so it is not recommended as standard salvage in low-risk disease [23]. High-risk GTN is treated with combination chemotherapy, most often EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), and immunotherapy with PD-1 inhibitors achieves complete responses above 70% in resistant disease; these regimens belong to the oncology domain and are not detailed here [23]. Cure in the British registration programme is 98–100% [25]. In 2026 FIGO published a revision of GTN staging, the content of which was not analysed in this review [145].

7.7. Contraception, subsequent pregnancy, and perioperative care

The RCOG advises against conceiving until follow-up is complete (C) and, after chemotherapy, waiting one year as a precaution; it refers contraception to the guidance of the Faculty of Sexual and Reproductive Health and accepts exogenous oestrogens, fertility drugs, and hormone replacement therapy after hCG normalisation (✓) [25]. FIGO considers hormonal contraception safe during post-molar follow-up and accepts telemedicine for surveillance [23]. After treatment of GTN, reliable contraception is mandatory during the at least 12 months of monthly hCG surveillance [23]. The 2005 Unique guide gave follow-up periods of 6 months to 2 years and a wait of 6 months of normal tests for women followed for 2 years; these intervals have been superseded by the 2020–2025 guidelines described in section 11 [23, 25, 30].

7.8. Diploid/triploid mixoploidy: management

Management of mixoploidy is symptomatic and multidisciplinary. Smith notes that a heel lift on the shorter leg may be needed to prevent compensatory scoliosis [3]. In the case of Mahon and colleagues, the child was followed by physiotherapy for central hypotonia with hypermobility, received palliative care planned prenatally and postnatally, and was later discharged; the authors suggest abdominal ultrasound as part of the postnatal evaluation, after finding a small hepatic haemangioma that regressed by 7 months [122]. The case of Lalani and colleagues shows that digestive manifestations (gastro-oesophageal reflux, laryngomalacia, decreased intestinal motility) may dominate the early years [95]. The truncal obesity, seizures, intellectual disability, and learning disabilities described call for nutritional, neurological, and developmental surveillance, for which the sources consulted provide no published protocols [3, 24].

7.9. Regulatory status

The actinomycin D pulse regimen (1.25 mg/m²), the 0.5 mg/day for 5 days regimen, and rescue with a single dose of folinic acid are FIGO 2025 recommendations; they do not appear in the labels consulted, so their use is off-label [23, 141, 143].

7.10. Evidence supporting decisions

There are no randomised clinical trials in triploidy. The table brings together the observational studies and syntheses that support surveillance and treatment decisions.

The data come from the sources cited [19, 20, 23, 25, 26, 139]. Their interpretation has limits. The zero rate of Scholz and colleagues is an estimate with an upper confidence limit of 1.4% and does not prove zero risk; the RCOG outcome "chemotherapy" and the FIGO outcome "progression" are not the same, the 0.5–5% range includes series with a morphological diagnosis of PHM without genotyping, and genotyping shows that about half of morphologically suspected PHMs are diploid [128]; the series of Worley and colleagues measures referred cases. Massalska and colleagues also cite 0 cases of GTN among 265 diandric triploidies in another series [20]. Comparing remission rates for actinomycin D and methotrexate across different trials is not valid, and FIGO itself notes that some studies used inferior methotrexate regimens [23].

7.11. Developments in the past 12 months

There are no therapeutic trials or regulatory procedures applicable to triploidy, and ClinicalTrials.gov was not searched for that reason; the search for recent developments was limited to Europe PMC and general searches, and absence of results does not prove absence of developments.

7.12. Guideline recommendations and divergences

The 2020 EOTTD flowcharts for minimum requirements and optimal practice, by Lok and colleagues, were updated by the 2025 global guideline [146, 149]. The 2016 German, Austrian, and Swiss S2k guideline covers GTD but was not read in full during data collection [150].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk

Triploidy is considered sporadic, and recurrence risks are very low, probably only slightly above the baseline risk [4, 74]. Its occurrence does not impair the couple's future reproduction, and maternal age is not a risk factor [12, 13, 73]. The Unique guide explains to families that, because triploidy is very common at conception, most repeat occurrences in the same woman will have happened by chance [30]. Smith records that, in several cases, a triploid pregnancy was preceded or followed by a molar pregnancy [3].

The Oxford Desk Reference figures for recurrence after two moles (15–18%) and those of Sebire and colleagues (about 10% after two complete moles) measure different populations and are not directly comparable [4, 148]. FIGO states that recurrence after PHM has not been observed, which diverges from the 1.7% of Sebire and colleagues; the primary source, with 2627 PHMs, supports a low but non-zero risk [23, 148]. Women who conceive after a mole are not at increased risk of maternal complications, but exposure to a mole before the index delivery was associated with a nearly 25% higher risk of preterm birth (odds ratio 1.23; 95% CI 1.06–1.43) and, when a delivery occurred between the mole and the index delivery, with more large-for-gestational-age births (1.35; 1.10–1.67) and stillbirths (1.81; 1.11–2.96) [25].

8.2. Evaluation of the couple

Parental karyotyping is not indicated after a triploidy, and Oxford Desk Reference, citing the 2011 RCOG Green-top Guideline 17, indicates it only after detection of a structural imbalance in the products of conception; recurrent miscarriage with normal parental chromosomes is not, in itself, an indication for genetics referral [4, 16]. In the Portuguese case of Fontoura Oliveira and colleagues, parental karyotypes were normal [74]. In the evaluation of recurrent miscarriage, Stephenson and colleagues karyotyped 420 specimens from 285 couples: 225 (54%) were euploid and 195 (46%) abnormal, of which 131 (66.5%) were trisomic, 37 (19%) polyploid, 18 (9%) 45,X, and 8 (4%) unbalanced translocations, with a distribution similar to that of controls after stratification by maternal age [151]. Oxford Desk Reference presents this study with a denominator of 225, inconsistent with the total of 420 in the primary source [16]. When the miscarriage is aneuploid, the probability of a successful subsequent pregnancy is higher than after a euploid miscarriage (68% vs 41% live births, in the Carp series cited by Oxford Desk Reference) [16].

With repeated triploidies, the authors of the reports propose genotyping the products of conception, to distinguish diandry from digyny and meiosis I from meiosis II, and exome sequencing in the woman; a finding of repeated maternal meiosis II failure suggests an oocyte predisposition [9, 10, 58, 60]. With repeated moles, tissue genotyping defines the next step: a biparental diploid mole leads to testing of NLRP7 and KHDC3L in the woman, and genetic testing with counselling is recommended for all women with recurrent moles [6]. NLRP7 accounts for 48–80% of women with two or more moles, and KHDC3L for 10–14% of those negative for NLRP7; in an Indian series, 20 of 23 women with recurrent moles and no live birth had biallelic NLRP7 variants [6, 7]. Women with two or more biparental diploid complete moles can be counselled as those with confirmed variants, even when no variant is identified [7]. In taking the family history, the GeneReviews MEG-MLID chapter recommends asking about relatives with moles, miscarriages, and infertility [14].

The sources diverge on the cancer risk of women with NLRP7 variants: in an Indian series, 50% of women with biallelic NLRP7 variants developed GTN, two to three times the rate after sporadic moles; Nguyen and colleagues (2014) state that these women have at least no greater risk of choriocarcinoma than after a sporadic mole, and the risk of neoplasia requiring chemotherapy has not been delineated [6, 7]. Each mole requires suction evacuation, histopathology with genetic analysis of the tissue, and serial hCG until undetectable, and subsequent pregnancies require early ultrasound (about 8 weeks) and hCG after they end [6].

8.3. Reproductive options

Prenatal diagnosis in a subsequent pregnancy after triploidy is discretionary and not specifically indicated, because most triploid conceptions are lost spontaneously; routine combined screening detected 83.3% of triploidies in Denmark [4, 71]. After a mole, the Danish guideline recommends early ultrasound, at about 8 weeks, in all subsequent pregnancies (D) [124].

In assisted reproduction, assessment of pronuclear number and time-lapse imaging reduce the transfer of triploid embryos (74.1% of 3PN embryos are triploid), and SNP-based PGT detects triploidy and genome-wide uniparental disomy, which read-count–based PGT-A does not detect [67, 68]. In families with oocyte meiotic failure, IVF with the woman's own oocytes may not yield mature oocytes: in the CCNB3 family, none of the 10 oocytes reached metaphase II and in vitro maturation failed, and pregnancy was achieved with donor oocytes [9]. In women with biallelic NLRP7 or KHDC3L variants, oocyte donation is the documented route to a normal pregnancy (3 additional live births in 2 women; 1 term delivery; in a 17-year prospective cohort of 23 women, 3 of 4 who underwent IVF with donated oocytes had a live birth), and PGT of the woman's own oocytes does not help [6, 7]. One woman who had delivered after oocyte donation again had a complete mole after a spontaneous conception, showing that donation does not change the risk of conceptions with her own oocytes [6].

8.4. Diploid/triploid mixoploidy

Diploid/triploid mixoploidy is postzygotic and sporadic, and Oxford Desk Reference recommends counselling as for complete triploidy [4, 21]. The sources consulted do not describe familial recurrence of mixoploidy; Wulfsberg and colleagues, cited by Smith, described monozygotic 2n/3n twin girls with pigmentary dysplasia [3]. Reproduction in adults with mixoploidy is not described in the sources consulted.

8.5. Content of counselling

Counselling should explain the difference between triploidy and trisomy, the accidental origin at conception, the absence of blame and of modifiable risk factors, the prognosis (lethal in the complete form; variable in mixoploidy), the relevance of parental origin to maternal and trophoblastic risk, the need for registration and hCG surveillance when there is a PHM, and the low recurrence risk, with its familial exceptions [15, 25, 30]. Perinatal bereavement and late fetal death require specific support, and patient organisations offer contact with families who have had the same experience [30, 31]. Counselling of minors does not apply to complete triploidy; in mixoploidy, diagnosis in childhood has consequences for developmental surveillance, not for the family's reproductive risk.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

Estimates of the frequency of triploidy vary across three orders of magnitude because they measure different stages of pregnancy and samples with different ascertainment.

The Orphanet figure of 12.6/100,000, classified as birth prevalence, corresponds in the source article to a total prevalence that includes terminations and fetal deaths, and not to live-birth prevalence, which the article does not report [1, 12]. In EUROCAT, the diagnosis was prenatal in 92% of cases, with detection before 14 weeks in 18%, between 14 and 21 weeks in 53%, at 22 weeks or later in 7% and at an unknown gestational age in 22% [12]. The frequency of diploid/triploid mixoploidy is unknown; Boonen and colleagues suggest underdiagnosis, because diagnosis requires non-haematological tissues [24, 96].

9.2. Diandric versus digynic proportion: the effect of ascertainment

The proportion of diandric cases ranges from 20% to 85% in the literature, and Massalska and colleagues attribute this range to selection bias: the preferential inclusion of abnormal placentas in the Zaragoza series and recruitment from a mole referral centre in the Joergensen series inflate diandry [44]. In Warsaw, diandry was 46.5% before 11 weeks, 64.3% between 11 and 14 weeks and 27.8% after 14 weeks; by sample type, 38.5% in chorionic villi, 23.5% in amniocentesis and 50.6% in curettage specimens [44]. Diandric cases accounted for 56% in Barcelona, 43% in Moscow, 30.4% in Amsterdam and 85% of confirmed cases with known origin on SNP-based cfDNA, which mainly detects diandric cases [17, 19, 112, 121]. Older cytogenetic studies showed a paternal predominance (69% paternal sets in Smith) and the first molecular studies in fetuses a maternal predominance, a discrepancy explained by the type of material analysed [3, 39, 40]. The operational conclusion is that, in the second trimester, diandric cases are at least half as frequent as digynic ones [44].

9.3. Trophoblastic disease: data by region

In the United Kingdom, the incidence of GTD is 1 in 714 live births, higher in women of Asian origin (1 in 387) than in other women (1 in 752); persistent GTD follows 15% of complete moles and 0.5–1% of partial moles, and the incidence after a term pregnancy is 1 in 40,000 to 1 in 50,000 [4, 25]. The risk of mole is twice as high below the age of 20 and above 35, and five to seven times higher above 40 [23]. Orphanet classifies the prevalence and incidence of hydatidiform mole and partial mole as unknown [2, 5].

9.4. United States, Europe, founder populations, Portugal and Brazil

North American data come mainly from the miscarriage series of Pittsburgh and Cleveland, the second-trimester triploidies of Iowa and North Carolina, the PHM series of a referral centre and the large SNP-based cfDNA datasets of a commercial laboratory [40, 75, 112, 139]. European data include EUROCAT, the Danish cohorts (screening, registry and triploid moles), Amsterdam, Warsaw, Barcelona, Vienna, Zurich, Slovakia and the British GTD registry [12, 19, 25, 26, 41, 43, 44, 70, 71, 121, 128]. No founder populations have been described for triploidy, which is consistent with its sporadic origin; for NLRP7-related recurrent mole, series with consanguinity (such as the Indian series in GeneGuidance) concentrate the cases, and Oxford Desk Reference recommends considering biallelic variants particularly when there is consanguinity [4, 6].

From Portugal, the sources consulted include the case of recurrent digynic triploidy reported by Fontoura Oliveira and colleagues (Centro Hospitalar do Médio Ave, with pathology at CGC Genetics, Porto) [74]. From Brazil, they include the scoping review on p57 published in the Revista Brasileira de Ginecologia e Obstetrícia and the phenotypic delineation of mixoploidy by Carakushansky and colleagues [98, 125]. The sources consulted provide no national frequencies for Portugal or Brazil, which does not demonstrate an absence of published data.

9.5. Special populations

In twin pregnancies, serum screening and cfDNA may give inaccurate results when one fetus has died, in a vanishing twin or when one of the fetuses has an anomaly, and a vanishing twin is the main cause of an extra fetal haplotype on SNP-based cfDNA [112, 113, 120]. In assisted reproduction, triploidy is much more frequent in embryos with an abnormal number of pronuclei [67]. In a pregnant woman with an organ transplant, the presence of donor DNA can mimic an extra haplotype [112]. Adolescents and women over 35 or 40 years of age are at increased risk of sporadic mole, but not of triploidy [12, 23].

9.6. European reference networks and patient organisations

ERN ITHACA covers rare malformation syndromes and intellectual disability [27]. EURACAN covers rare adult solid tumours, with a gynaecological domain, but explicit inclusion of GTD is not described on the page consulted; trophoblastic disease is organised through national reference centres and the EOTTD and ISSTD societies and, in the United Kingdom, through the Charing Cross and Weston Park services [25, 28, 29, 152, 153]. Patient organisations include Unique (triploidy guide), Molar Pregnancy Support & Information, cited by the RCOG, the Miscarriage Association, SOFT (trisomies 18 and 13 and related disorders) and, in the United Kingdom, Antenatal Results and Choices (ARC) and the Stillbirth & Neonatal Death Society (Sands), mentioned in the Unique guide [30–32, 154].

10. Illustrative Clinical Case

10.1. Recurrent fetal triploidy with a digynic phenotype (Portugal)

Fontoura Oliveira and colleagues described a White woman taking ethyl loflazepate for anxiety, with no consanguinity or relevant family history, who had three spontaneous pregnancies [74]. At the age of 29 she had a normal pregnancy, with a healthy term baby girl; at 32 and 34 she had two triploid pregnancies, electively terminated in the second trimester, and the article abstract attributes the two triploidies to different fathers, although the full text is ambiguous regarding the paternity of the pregnancies [74].

In the first triploidy, screening at 12 weeks showed PAPP-A of 0.03 MoM, free β-hCG of 0.25 MoM and normal NT, with a screen positive for trisomy 18 and negative for trisomy 21. At 18 weeks there was oligohydramnios, severe asymmetric FGR (weight below the 5th centile), a disproportionately large head circumference and hypertelorism; amniocentesis revealed 69,XXY and the pregnancy was terminated at 19 weeks. Autopsy showed a small, macrocephalic fetus with hydrocephalus, cerebellar vermis hypoplasia, hypertelorism, proptosis, low-set ears, bulbous nose, severe micrognathia, left talipes, clenched hands with left 2–3 syndactyly, female external genitalia despite the 69,XXY karyotype and a single umbilical artery; the placenta was of low weight, without macroscopic changes, and showed severe chronic intervillositis (Fig. 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC7929808/figure/F1/) [74].

In the second triploidy, screening at 11 weeks showed PAPP-A of 0.028 MoM, free β-hCG of 0.219 MoM and normal NT, with a negative combined screen. At 22 weeks there was severe oligohydramnios, severe FGR (below the 1st centile), a relatively large head and a posterior fossa malformation with vermian agenesis; amniocentesis revealed 69,XXX and the pregnancy was terminated at 23 weeks. Autopsy showed a small female fetus with a large head, hypertelorism, proptosis, low-set ears, small nose, micrognathia, bilateral talipes and syndactyly (3–4 on the left and 2–3 on the right); autolysis precluded examination of the brain; there was a single umbilical artery with eccentric insertion and a very-low-weight placenta without abnormalities (Fig. 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC7929808/figure/F2/) [74].

Parental karyotypes were normal (46,XX and 46,XY). No molecular testing of origin was performed: digyny was inferred from the phenotype (very low PAPP-A and free β-hCG, small placenta, FGR with a large head and survival into the second trimester), and the woman was referred to a preconception clinic and for genetic counselling [74].

The case illustrates three points. First, the digynic biochemical pattern recurred from one pregnancy to the next and matches the medians of genotyped cohorts (PAPP-A 0.05 MoM and free β-hCG 0.27 MoM in Amsterdam) [19]. Second, combined screening for trisomies can be negative in digynic triploidy, as happened in the second pregnancy, even though Danish screening detected 83.3% of triploidies [71]. Third, recurrence in a woman with different partners points to a maternal factor, and the work-up proposed in the recent literature would include tissue genotyping to establish digyny and meiosis I or II and, if repeated maternal meiotic failure were confirmed, exome sequencing in the woman, as in the families with CCNB3 or HORMAD2 variants [9, 10, 58]. The absence of origin testing differs from current proposals, which recommend genotyping also to exclude a PHM and to decide on hCG surveillance [19, 127].

10.2. Diploid/triploid mosaicism diagnosed in buccal mucosa (Ireland)

Mahon and colleagues reported a pregnancy with severe FGR (weight below the 1st centile between 20 and 31 weeks) in which amniocentesis at 20 weeks showed 69,XXX in 6 of 30 cells and 46,XX in 24, with QF-PCR suggesting digynic origin [122]. Delivery occurred at 39+4 weeks, with a birth weight of 2040 g (below the 1st centile), head circumference of 32.5 cm (8th centile) and Apgar scores of 9/9; the baby girl had a small mouth and chin, high palate, single palmar crease, low-set ears and central hypotonia, and was discharged on day 4 with oral feeding. The placenta was hypoplastic (272 g, below the 3rd centile) with normal histology, and a small hepatic haemangioma regressed by 7 months. Postnatal blood karyotype and microarray were normal; FISH on a buccal smear, with centromeric probes for chromosomes 8 and 9, showed three copies in 38 of 100 cells. At 4 months, weight was 4290 g (0.01st centile) and head circumference was on the 17th centile; at 15 months, central hypotonia with hypermobility persisted, without crawling or standing, with physiotherapy follow-up. The family received palliative care support prenatally and postnatally, with subsequent discharge [122]. The article page consulted had no figures. The case documents that a normal blood result does not exclude the diagnosis and that the prognosis of mixoploidy is variable and difficult to predict [122].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In complete triploidy, the fetal prognosis is lethal: the vast majority are lost in the first trimester, pregnancies that reach the third trimester end in intrauterine or neonatal death, only 3% of EUROCAT cases were live born, and the longest published survivor lived 10.5 months [4, 12, 18]. In modern prenatal series without termination, there were no live births [19, 70]. The maternal prognosis is favourable but depends on the origin: complications (hyperemesis, hyperthyroidism, theca lutein cysts, early hypertension) are concentrated in diandric triploidy, and bleeding is more frequent in digynic triploidy [20]. After a PHM, the risk of GTN is low (chemotherapy in 0.5–1.0% in the United Kingdom; 0.5–5% according to FIGO; 0/154 in a Danish cohort of triploid moles), and the cure rate for GTN in the British programme is 98–100%, with fertility preserved in most women [23, 25, 26, 155]. Smith's statement that PHM with a triploid fetus should not raise concern about choriocarcinoma is at odds with current guidelines, which require registration and hCG surveillance for all PHMs; Oxford Desk Reference reports choriocarcinoma in about 0.1% of PHMs [3, 4, 25]. hCG normalisation after diandric triploidy beyond 13 weeks took a mean of 84 days (11–142), with one case taking more than 20 weeks, and 2 to 8 months after triploid PHM in Amsterdam, with no cases of GTN [19, 20].

In diploid/triploid mixoploidy, survival is better, but neurodevelopment is usually affected (psychomotor delay, learning disabilities, seizures, intellectual disability), with short stature, truncal obesity, scoliosis and asymmetry; the proportion of triploid cells does not predict the degree of asymmetry, and in the series of Carson and colleagues only 1 of 8 cases resulted in a healthy live birth [3, 21, 36, 57]. The adult phenotype has been described in isolated cases [94].

11.2. Surveillance table

The intervals in the table match those described in section 7, and the differences among the RCOG, FIGO and the Danish guideline reflect the choices of each health system rather than comparative evidence. In the absence of genotyping confirming a non-molar digynic triploidy, FIGO accepts hCG surveillance of suspected PHMs [19, 23].

12. Summary and Concluding Remarks

Triploidy is one of the most frequent chromosome abnormalities at conception and one of the main causes of spontaneous miscarriage, but it rarely reaches birth: the total European prevalence is 1.26 per 10,000 births, almost always with prenatal diagnosis, and the complete form has no survival beyond the first year [12, 18]. The most useful clinical datum is the origin of the extra set. Diandric triploidy, almost always due to dispermy, is associated with a large cystic placenta, partial mole, markedly elevated β-hCG, increased NT and maternal complications ranging from hyperemesis and hyperthyroidism to early-onset pre-eclampsia; digynic triploidy, due to an error in maternal meiosis II or I, is associated with severe asymmetric FGR with relative macrocephaly, a small placenta and very low PAPP-A and free β-hCG, with no trophoblastic risk of its own [19, 20, 41, 42].

Diagnosis rests on karyotype, QF-PCR or SNP microarray, not on aCGH, which does not detect triploidy; cfDNA flags it only with SNP-based methods, with limited predictive value, and requires invasive confirmation [16, 112, 119]. Parental origin is determined by genotyping with a parental sample or by MS-MLPA, and in products of conception histology with p57 should be supplemented by genotyping, because morphology fails to classify a relevant fraction of partial moles [22, 126, 127]. Every PHM is registered and monitored with hCG; the risk of GTN is low, and guidelines diverge on the end of follow-up (two normal samples 4 weeks apart in the RCOG, one confirmatory test 1 month later in FIGO, two undetectable values in Denmark) [23, 25, 124].

Recurrence is low, but there are familial exceptions that justify genotyping repeated conceptions: maternal meiosis II failure with CCNB3 or HORMAD2 variants in isolated families, and biallelic NLRP7 or KHDC3L variants in recurrent moles, in which oocyte donation is the documented route to a normal pregnancy [6, 9, 10]. Diploid/triploid mixoploidy is a postnatal entity diagnosed in tissue, suggested by asymmetry, 3–4 syndactyly and pigmentation along the lines of Blaschko, with normal blood in about three-quarters of cases and a variable developmental prognosis [21, 24, 122].

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