Recurrent Pregnancy Loss - Genetic Causes

Reciprocal and Robertsonian translocations, inversions, aneuploidies and polyploidies of the products of conception, confined placental mosaicism, lethal fetal monogenic variants and recurrent hydatidiform mole due to biallelic maternal variants; hereditary thrombophilias and antiphospholipid syndrome as differential diagnoses.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Terminology and evolution of the definition

The term “miscarriage” (used mainly as a lay term in English-language literature) refers to spontaneous pregnancy loss before viability. The 2017 Oxford Desk Reference distinguishes early pregnancy loss (EPL), before 12 weeks, from spontaneous abortion in the broader sense, before 24 weeks; “blighted ovum” denotes a gestational sac without fetal parts on ultrasonography, missed abortion the presence of fetal parts without cardiac activity before 24 weeks, and intrauterine fetal death fetal death after 24 weeks and before labour [5]. ESHRE (European Society of Human Reproduction and Embryology) defines pregnancy loss as spontaneous pregnancy demise before viability, including all losses from conception to 24 weeks, and acknowledges that definitions differ between countries [1]. ASRM (American Society for Reproductive Medicine), in its 2026 committee opinion, adopts the international glossary's 22-week threshold and classifies losses from 22 weeks as stillbirths, outside its scope [3]. ACOG (American College of Obstetricians and Gynecologists) defines early pregnancy loss as a non-viable intrauterine pregnancy up to 12 weeks and 6 days [30].

The definition of recurrent pregnancy loss has changed. The 2017 Oxford Desk Reference still defines it as three or more consecutive spontaneous miscarriages [5], and RCOG (Royal College of Obstetricians and Gynaecologists) retains the definition of three or more first-trimester miscarriages in its 2023 Green-top Guideline No. 17, without requiring them to be consecutive or with the same partner, although it allows expanded evaluation after two miscarriages when a pathological cause is suspected, for example loss of a fetus with normal non-invasive prenatal testing (NIPT) or karyotype [2]. ESHRE, in its 2022 update published in final form in January 2023, concluded after debate that “a diagnosis of RPL can be considered after the loss of two or more pregnancies”; some group members disagreed and retained the criterion of three consecutive losses [1]. The rationale is empirical: the number of losses (two or three) and whether they are consecutive do not alter the probability of antiphospholipid syndrome or of either partner carrying a structural chromosomal abnormality, the distribution of associated factors is the same with two or three or more losses, and fewer than 10% of couples have non-consecutive losses [1]. For ESHRE, pregnancy must be confirmed by serum or urinary hCG measurement, including non-visualised losses (biochemical pregnancies and resolved or treated pregnancies of unknown location), excluding ectopic pregnancies, identified molar pregnancies and implantation failures, and including losses after spontaneous conception or assisted reproductive technology (ART) [1]. Primary RPL occurs without a previous ongoing pregnancy beyond 24 weeks, and secondary RPL after at least one pregnancy of that duration [1].

In 2026, ASRM replaced the 2012 document defining RPL as two or more failed clinical pregnancies, and the 2020 definition, with a definition of two or more spontaneous losses, excluding only confirmed molar or ectopic pregnancies; a urinary or serum hCG test is sufficient, without requiring ultrasonography or histological confirmation, because biochemical losses have a similar impact on recurrence risk; losses need not be consecutive, and RPL is treated as a disease distinct from infertility [3, 31, 32]. SOGC (Society of Obstetricians and Gynaecologists of Canada), in its 2025 guideline No. 464, also adopts a two-loss threshold, including non-consecutive and biochemical losses [4]. The current definition of two or more losses shared by ESHRE, ASRM and SOGC thus differs from the Oxford Desk Reference definition of three or more consecutive losses and the RCOG definition of three miscarriages; prevalence and diagnostic yield figures in each study must be read in light of its definition [1–3, 5].

1.2. Historical and molecular milestones

The concept that most first-trimester miscarriages are due to embryonic aneuploidy rests on cytogenetic studies of miscarriage tissue in the late 1970s and 1980s, including Hassold and colleagues (1980), cited by ASRM as the basis for estimating that 50–60% of first-trimester miscarriages are aneuploid [3]. In 1990, De Braekeleer and Dao, studying more than 22,000 couples with two or more spontaneous miscarriages in Québec, showed that one partner carried a chromosomal rearrangement in 4.7% of cases, compared with 0.5% in the reference population [5]. In 2001, Robinson, McFadden and Stephenson studied 54 couples with two or more documented aneuploid or polyploid miscarriages and concluded that recurrent trisomy results mainly from maternal age-related meiotic errors, even when the second miscarriage had the same abnormality, without a significant role for germline mosaicism, segregation factors or sperm aneuploidy [5, 33]. In 2002, Stephenson, Awartani and Robinson successfully karyotyped 420 specimens from 285 couples with recurrent miscarriage, of which 225 (54%) were euploid and 195 (46%) abnormal [34]; the Oxford Desk Reference describes this as a “study of 225 POC”, confusing the euploid count with the total [5, 34].

The first human maternal-effect gene was identified in 2006, when Murdoch and colleagues described five NALP7 (now NLRP7) variants in women with familial recurrent hydatidiform mole, also associated with repeated spontaneous miscarriages, stillbirths and intrauterine growth restriction (IUGR) [35]. In 2011, Parry and colleagues identified biallelic C6orf221 (now KHDC3L) variants in three families with familial biparental hydatidiform mole, the only known human disorder with a pure recessive maternal effect [15]. MEI1 and TOP6BL were associated with recurrent hydatidiform mole types 3 and 4 [10], and the 2022 expert consensus recognises seven maternal-effect genes with causal variants for recurrent mole, retaining NLRP7 as the main gene [36]. In 2019, low-coverage genomic sequencing in 1090 Chinese couples with recurrent miscarriage showed that approximately one in nine couples had a chromosomal abnormality, 39.7% undetected by conventional karyotyping [37]. Since then, exome and genome sequencing have been applied to euploid losses and fetuses with structural anomalies [38–40], and in 2026 a curated database of 934 genes essential for human viability was published to support interpretation of these analyses [41].

1.3. Scope of this article

This article covers the genetic causes of RPL: POC aneuploidy and polyploidy, parental balanced structural rearrangements (reciprocal translocations, Robertsonian translocations and inversions), confined placental mosaicism, lethal fetal monogenic variants and recurrent hydatidiform mole due to biallelic maternal variants, with the other maternal-effect genes as context. Hereditary thrombophilias and antiphospholipid syndrome (APS) are covered as differential diagnoses and as examples of genetic tests without clinical utility in this setting. Prenatal diagnosis, mosaic trisomy 16, CPM and uniparental disomy (UPD) 16, hereditary thrombophilias and infertility, including embryo developmental arrest due to maternal-effect genes, appear here insofar as they bear on recurrent pregnancy loss.

2. Molecular Genetics and Pathophysiology

2.1. Aneuploidy of the products of conception

Chromosomal abnormality in the conceptus is the most frequent cause of sporadic and recurrent miscarriage [2]. At least 50% of miscarriages have a chromosomal abnormality, and proportions rise to 60–70% when chromosomal microarray (CMA) is used on chorionic villi sampled at diagnosis of the loss or samples that failed to grow in culture [5]. Table 2.1 summarises the classical distribution of abnormality types in spontaneous miscarriage according to the Oxford Desk Reference, and the review cited by RCOG gives a similar distribution: trisomy 51.9%, polyploidy 18.8%, monosomy 15.2%, structural abnormalities 6.5% and others 7.6% [2, 5].

Table 2.1. Most common chromosomal abnormalities in spontaneous miscarriage [5]

Aneuploidy results mainly from segregation errors in maternal meiosis and increases with the woman's age. In the ASRM data, aneuploidy is present in approximately 50% of tested miscarriages in women under 35 years and 75% of miscarriages in women over 40 years [3]. A series of 1585 miscarriage tissues analysed by CMA in Urumqi (China, 2019–2025) found chromosomal abnormalities in 54.44%, with trisomy 16 and monosomy X the most frequent, a U-shaped relationship with maternal age (minimum risk at 28–29 years; odds ratio, OR, 1.72 with a 95% confidence interval, 95% CI, of 1.31–2.26 for age 35 years or older) and a peak in abnormalities at 8–10 weeks, with gestational age of 12 weeks or more being protective (OR 0.27; 95% CI 0.21–0.34) [42]. Aneuploidy is also found in 20% of stillbirths at 22 weeks, 6% of term stillbirths and 0.1–5% of term live births, according to data cited by ASRM [3].

Aneuploidy is equally frequent in sporadic and recurrent loss, but the proportion of euploid miscarriages increases with the number of losses. The systematic review cited by ESHRE estimated the prevalence of chromosomal abnormalities at 45% (95% CI 38–52; 13 studies; 7012 samples) in sporadic miscarriage and 39% (95% CI 29–50; 6 studies; 1359 samples) in a miscarriage following RPL [1]; the review cited by RCOG gives 49.7% (95% CI 34.9–64.6) in sporadic miscarriage and 40.4% (95% CI 25.2–55.7) in recurrent miscarriage [2]. In the case–control study by Stephenson and colleagues, the 195 abnormal miscarriages in couples with recurrent miscarriage included 131 trisomies (66.5%), 37 polyploidies (19%), 18 monosomies X (9%), 8 unbalanced translocations (4%) and one case with trisomy 21 and monosomy X; euploidy was significantly more frequent in women under 36 years with recurrent miscarriage than in controls, and the distribution of abnormalities was the same as in controls when stratified by maternal age [34]. ASRM concludes that, compared with isolated miscarriage, patients with RPL are more likely to have euploid miscarriage, and that this probability increases with the number of miscarriages [3]. Miscarriages after ART have a frequency of cytogenetic abnormalities similar to sporadic miscarriages (56.8% versus 53.6%; OR 1.11; 95% CI 0.71–1.73) [2].

Beyond aneuploidy, embryoscopy shows morphological abnormalities in 86–91% of miscarriages in which an embryo is present [1], and in 18% of missed miscarriages with a normal karyotype [2], suggesting submicroscopic or monogenic causes in some euploid miscarriages. Molecular techniques add 5–7% submicroscopic variants, and microarray identified abnormalities in as many as 59.4% (1106/2389) of sporadic miscarriages in one series cited by RCOG [2].

2.2. Polyploidy: triploidy, tetraploidy and hydatidiform mole

Approximately 7.5% of spontaneous miscarriages are triploid. Unlike aneuploidies due to nondisjunction, advanced maternal age is not a risk factor, and the mechanism is poorly understood [6]. Digynic triploidy (69,XXX or 69,XXY) has two maternal chromosome sets and one paternal set, through incorporation of the second polar body into the fertilised oocyte; diandric triploidy (69,XXX, 69,XXY or 69,XYY) has two paternal sets and one maternal set, through dispermy [6]. The classical study by Jacobs and colleagues (1982) estimated triploidy in 1–2% of all pregnancies, and a Danish registry counted 183 triploid pregnancies among 1.5 million clinically confirmed pregnancies, most associated with molar disease, with 29 fetuses alive on ultrasound before termination; soft tissue syndactyly and asymmetric IUGR were common, and some fetuses were almost normal [6]. Diploid/triploid mosaicism results from late digyny (incorporation of the pronucleus of the second polar body into a blastomere) or late dispermy; one reported case was a chimera through fusion of two zygotes and in another the triploid cell line was confined to the placenta [6].

Partial hydatidiform mole contains embryonic or fetal tissue, villi of variable size with focal oedema, cavitation and trophoblastic hyperplasia, and is diandric triploid in 90–93% of cases; complete mole is 46,XX in 90% of cases, with exclusively paternal chromosomes [6]. The usual mechanism of complete mole is fertilisation of an oocyte without genetic material by one sperm that duplicates its genome (monospermic diandry), or more rarely by two sperm; 75–85% of complete moles are 46,XX and the remainder 46,XY [43]. The shared pathogenic hypothesis is that excess paternal genome and lack of an imprinted maternal contribution favour trophoblastic proliferation at the embryo's expense [6, 15].

2.3. Reciprocal translocations

In a balanced rearrangement, the amount of genetic material is normal; in an unbalanced rearrangement, there is additional material, missing material, or both [13]. Balanced autosomal reciprocal translocations are common (more than 0.1% of the population), and most are unique to a family; t(11;22)(q23;q11) is the most frequent recurrent non-Robertsonian translocation [13, 44]. A rearrangement that appears balanced on G-banding (typical resolution 5–10 Mb) is described as “apparently balanced”, because an imbalance may be detectable by array or exome sequencing; in a phenotypically normal carrier it is assumed to be truly balanced [13].

During meiosis, the four chromosomes involved pair in a quadrivalent. Alternate segregation produces normal or balanced gametes; adjacent-1 segregation gives the smallest imbalance when the translocated segments are shorter than the centric segments and is the most common pattern of viable imbalance (70%); adjacent-2 gives the smallest imbalance when the translocated segments are longer than the centric segments and is uncommon (5% of viable imbalance); 3:1 segregation gives the smallest imbalance when one chromosome (normal or derivative) is very small, produces interchange or tertiary trisomies, accounts for approximately 25% of viable imbalance and is more common in female carriers [13]. In female t(11;22)(q23;q11) carriers, 3:1 segregation occurs in 5–10% of offspring and produces Emanuel syndrome, with duplication 11q23→qter and 22pter→q11 [44]. Data on 261 products of conception and offspring of 203 reciprocal translocation carriers in Pittsburgh (113 women and 90 men) showed that translocations involving an acrocentric chromosome increase 3:1 segregation, that female carriers have a greater risk of additional aneuploidy through an interchromosomal effect, that there are few euploid embryos because of abnormal segregation at the first meiotic division, nondisjunction at the second and additional aneusomies, and that carriers with RPL have more miscarriages of euploid fetuses carrying the translocation [45].

The viability of the unbalanced product depends on segment size and gene content. Monosomy is much less tolerated than trisomy of similar size, monosomy of an entire autosome is never viable and trisomy of an entire autosome is viable only for chromosomes 13, 18 and 21 [13]. Expressed as a percentage of haploid autosomal length (HAL), 95–96% of published viable autosomal imbalances fall within a triangle bounded by 4% trisomy (approximately 120 Mb) and 2% monosomy (approximately 60 Mb); outside that triangle, the likely outcome is pregnancy loss, with the caveat that gene density and dosage sensitivity are not uniform [13]. This gives four possible outcomes in a carrier's pregnancy: normal karyotype, balanced translocation like the parent's, non-viable unbalanced product (pregnancy loss) and viable unbalanced product (child with a high probability of intellectual disability, with or without congenital anomalies) [13]. ESHRE estimates that, in couples with a parental chromosomal abnormality, approximately one-third of losses are due to the abnormality itself; the remainder are aneuploidies, unexplained losses or losses due to other factors [1].

2.4. Robertsonian translocations

Robertsonian translocations involve the acrocentrics 13, 14, 15, 21 and 22: the fused chromosome contains both long arms and loses some or all of the short arms, which contain nucleolar organiser regions present in other copies, without phenotypic effect [14]. The balanced carrier has 45 chromosomes; correct nomenclature is, for example, 45,XX,rob(14;21)(q10;q10), abbreviated 45,XX,rob(14q21q) [14]. The population frequency is approximately 1/1000, and the most common, rob(13q14q), occurs in approximately 1/1300 [14]. De novo forms arise mainly during oogenesis; non-homologous forms, such as rob(13q14q), are distinguished from homologous forms, such as rob(13q13q), which may result from fusion of maternal and paternal homologues in the zygote or from an isochromosome [14].

During meiosis, alternate segregation produces normal and balanced gametes and adjacent segregation produces disomic and nullisomic gametes; monosomic conceptions are lost, often before pregnancy is clinically recognised, trisomies 14 and 15 invariably miscarry, as do most trisomies 22, many trisomies 13 and some trisomies 21 [14]. In female der(13;14) carriers, the miscarriage rate was 28%, and 20% in partners of male carriers, in a series of 101 pedigrees [14]. Among carrier oocytes studied during preimplantation diagnosis, 33% were unbalanced, 51% normal and 16% balanced for rob(13q14q) (n=69), and 42%, 37% and 21%, respectively, for rob(14q21q) (n=86) [14]. In men, fluorescence in situ hybridisation (FISH) in sperm shows 3.4–36% abnormal sperm in carriers, versus approximately 6.7% disomic sperm in 46,XY men, and der(13;14) carriers are overrepresented 5–10-fold among infertile couples with oligospermia [14].

The main phenotypic risks in offspring are translocation trisomy 13 or 21 and UPD 14 or 15. Trisomy rescue, namely mitotic loss of the free homologue in a trisomic conception, produces a balanced karyotype that may have UPD [14]. Among 174 acrocentric rearrangements detected prenatally, UPD occurred in 1/168 (0.6%) non-homologous Robertsonian translocations and in 4/6 homologous rearrangements; in another series of 315 cases following prenatal diagnosis of a balanced Robertsonian translocation, 2 had UPD (0.65%) [14]. Paternal UPD14 corresponds to Kagami-Ogata syndrome (polyhydramnios, small thorax with “coat-hanger” ribs, severe developmental delay, contractures); maternal UPD14 to Temple syndrome (pre- and postnatal growth restriction, small hands and feet, hypotonia, precocious puberty in some cases, normal intelligence or mild intellectual disability); maternal UPD15 to Prader-Willi syndrome and paternal UPD15 to Angelman syndrome [14]. At least 50% of Robertsonian translocations between homologues show UPD, and an isochromosome has a 100% risk of UPD [14]. When an unbalanced Robertsonian translocation is identified in a child with trisomy 21, both parents should be studied, and one of them is a balanced carrier in approximately one third of cases; with normal parental karyotypes, the recurrence risk is very low (probably below 1%) and reflects the possibility of gonadal mosaicism undetectable in peripheral blood, whereas in a carrier parent the risk is higher, depends on the sex of the carrier and is lower than the theoretical risk, because of the frequent prenatal lethality of autosomal trisomies [46].

2.5. Inversions

An inversion results from two breaks in a chromosome with 180° rotation of the intervening segment; it is pericentric when it includes the centromere and paracentric when confined to one arm, and has no phenotypic effect unless material is lost or a gene disrupted [47]. In pericentric inversion carriers, unbalanced gametes result from crossing-over within the inversion loop and carry duplication of one distal segment and deficiency of the other; risk is specific to each inversion and higher when the potential imbalance is small and documented as viable [47]. Large pericentric inversions with small distal segments may produce viable recombinants, whereas those with large distal segments give larger imbalances contributing to infertility or miscarriage with a low risk of an unbalanced live birth; small inversions rarely form a loop, and polymorphic pericentric variants do not affect fertility or offspring [47]. Paracentric inversions are mostly harmless because dicentric or acentric recombinants are rarely viable; on G-banding they are difficult to distinguish from paracentric insertions, whose risk of viable imbalance is approximately 15%, and FISH may help [47]. Submicroscopic parental inversions between low-copy repeats predispose to deletions in genomic disorders such as Angelman and Williams syndromes [47].

2.6. Confined placental mosaicism

Mosaicism denotes the presence, in the same conceptus, of two or more cell populations with an acquired genetic difference, through mitotic nondisjunction, trisomy rescue or somatic mutation [48]. It is found in 0.3% of amniocenteses and in just over 2% of chorionic villus samples (CVS), with CPM in 1.9% and true fetal mosaicism in 0.19% [48]. CPM is classified as type 1 (cytotrophoblast only, seen in direct short-term preparations), type 2 (extraembryonic mesoderm only, seen in long-term culture) and type 3 (both) [48]. Mosaicism involving chromosomes 6, 7, 11, 14, 15, 16 or 20 requires consideration of fetal UPD and imprinting syndromes; mosaic trisomy 16, generally through trisomy rescue, is associated with placental abnormality, IUGR from 16 weeks and heart disease [48]. CPM is relevant to RPL because an abnormal villous result may not reflect the fetus and because trisomy rescue may leave UPD in a fetus with a normal karyotype.

2.7. Maternal-effect genes and recurrent hydatidiform mole

Maternal-effect genes are highly expressed in the oocyte and required to establish or maintain imprinting in the oocyte, zygote and early embryo; the woman with biallelic variants is healthy, and disease is expressed in her pregnancies, regardless of the genotype of the conceptus, which is heterozygous [7, 8]. NLRP7 belongs to the CATERPILLER family, associated with inflammation and apoptosis, regulates interleukin 1β secretion and forms part of the oocyte's subcortical maternal complex (SCMC) [35, 43, 49]. Loss of NLRP7 disrupts SCMC assembly, methylation of maternal differentially methylated regions, trophoblast differentiation and HLA-C-dependent immune privilege [49]. KHDC3L is expressed mainly in germinal vesicle-stage oocytes, declines until metaphase II and becomes undetectable after the oocyte-to-embryo transition; it forms part of a chromosome 6 gene cluster specific to eutherian mammals [15], and pathogenic variants cause loss of genomic methylation in oocytes, with imprinting defects persisting after fertilisation [9].

The consequence is biparental hydatidiform mole: molar tissue from women with biallelic NLRP7 or KHDC3L variants is diploid and has maternal and paternal contributions, unlike sporadic complete mole, which is androgenetic [15, 25]. Failure to establish maternal imprints at multiple loci causes the conceptus to behave as though its genome were exclusively paternal: the trophoblast proliferates and the embryo dies early [15]. In an analysis of 80 new molar tissues and a review of 123 tissues and 113 patients, all moles from patients with biallelic NLRP7 or KHDC3L variants were biparental diploid; in patients without variants, only 8% were biparental diploid, 24% monospermic androgenetic diploid and 32% dispermic triploid, and the remainder were misclassified [25]. Biallelic NLRP7 and KHDC3L variants account for 50–80% of patients with recurrent mole, defined as two or more moles in the same woman [25], and KHDC3L accounts for 10–14% of patients without NLRP7 variants [9]. NLRP7 and KHDC3L variants also confer a complete mole phenotype on digynic triploid conceptions [6]. Affected women also have spontaneous miscarriages, stillbirths and IUGR [8]. A 2026 review proposes a model of “genetic permissiveness” in which complete loss of NLRP7 function makes the probability of normal pregnancy almost zero, whereas missense variants with residual function allow rare normal pregnancies; the model has not been prospectively validated [49, 50].

Beyond mole, maternal-effect genes are associated with multilocus imprinting disturbances (MLID) in offspring. Table 2.2 summarises genes with offspring with MLID described in GeneReviews; counts refer only to families with MLID in offspring, not to the total number of women with NLRP7-related recurrent mole, which is much larger [7].

Table 2.2. Maternal-effect genes with biallelic maternal variants and offspring with MLID [7]

MLID occurs almost exclusively in imprinting disorders due to loss of methylation: in 25% of BWSp due to loss of methylation at KCNQ1OT1:TSS-DMR, 12.5% of GNAS inactivation disorders (pseudohypoparathyroidism 1B), 7–10% of SRS due to loss of methylation at H19/IGF2:IG-DMR, isolated cases of Temple syndrome and 60% of transient neonatal diabetes due to loss of PLAGL1 methylation [7]. Other maternal-effect genes have reproductive phenotypes overlapping RPL: NLRP2 (biallelic variants in 5 of 496 women with early embryonic arrest), NLRP5 (mothers of offspring with MLID and reproductive loss; biparental placental mesenchymal dysplasia), PADI6 (preimplantation embryonic lethality, with recurrent miscarriage and mole also described) and TLE6 (preimplantation lethality in 4 of 28 cases, 14.3%, and 3.19% in an embryonic arrest cohort) [11, 51–53]; their investigation is part of the genetic approach to infertility. A 2026 review of maternal variants associated with aneuploid conceptions identified the highest-quality evidence for rare likely pathogenic variants in KIF18A, ELL3 and CEP120 and for common variants in PLK4 and CCDC66, and considered that genes included in commercial infertility panels (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, TLE6) require validation of their direct association with aneuploidy [54].

2.8. Fetal monogenic causes

In X-linked dominant disorders with male lethality, such as incontinentia pigmenti (IKBKG), Goltz syndrome (focal dermal hypoplasia) and orofaciodigital syndrome type 1 (OFD1), affected male fetuses are spontaneously lost; the Oxford Desk Reference includes in the same group of disorders with very severe manifestations in males, potentially leading to spontaneous loss or neonatal death, Rett syndrome (MECP2) and otopalatodigital syndromes types 1 and 2 (FLNA); an affected heterozygous woman has four equally likely possibilities at conception, but only three are observed at birth (normal daughter, affected daughter, normal son) [5, 16]. These disorders are rarely the presenting concern and account for a very small fraction of RPL [5].

Fetal akinesia sequence is an example of recurrent monogenic fetal lethality, with causes in the brain, anterior horn (lethal congenital contracture syndrome due to GLE1, more common in Finland), peripheral nerve (CNTNAP1, ADCY6, GPR126), neuromuscular junction (CHRNG, causing lethal multiple pterygium syndrome; RAPSN; DOK7; CHRND; CHRNA1), muscle (autosomal recessive RYR1 in 8% of one cohort; ACTA1, NEB, KLHL40), metabolic disorders (glycogen storage diseases IV and VII), restrictive dermopathy (LMNA, ZMPSTE24) and Neu-Laxova syndrome (PHGDH, PSAT1) [55]. Recurrent affected pregnancies without intervening healthy children may be due to maternal antibodies against the acetylcholine receptor, even in asymptomatic women [55]. Inborn errors of metabolism interfering with the synthesis or catabolism of complex molecules (some lysosomal and peroxisomal disorders, cholesterol biosynthesis defects, RASopathies) manifest prenatally as non-immune hydrops fetalis, severe IUGR, visceromegaly or hyperechogenic kidneys, whereas amino acid or organic acid “intoxication” disorders do not interfere with embryofetal development [56]. In the systematic review by Colley and colleagues of euploid miscarriages up to 20 weeks, putatively causal CHRNA1, DYNC2H1 and RYR1 variants recurred in several studies, but there is no established diagnostic panel [38]. The “Human Intolerome” database comprises 934 genes essential for human viability: 59 (6.3%) associated with first- or second-trimester miscarriages, 525 (56.2%) with stillbirth or neonatal death and 350 (37.5%) lethal at any stage; it has documented de novo inheritance in 159 autosomal dominant genes and identifies 39 autosomal recessive genes with potentially lethal heterozygous variants at a frequency of 1/100 or more across all ancestries in gnomAD v4.1.0 [41].

2.9. Hereditary thrombophilias: mechanism and strength of association

Factor V Leiden (FVL) makes activated factor V resistant to inactivation by activated protein C and is the main genetic factor for venous thromboembolism (VTE); the prothrombin variant in the 3′ untranslated region increases plasma prothrombin concentration [1, 12]. The hypothesis that these variants cause pregnancy loss through placental thrombosis led to their inclusion in RPL assessment, but the association is weak. In the meta-analysis of 10 prospective cohorts, pregnancy loss occurred in 4.2% of women with FVL and 3.2% of women without FVL (OR 1.52; 95% CI 1.06–2.19), without an association with pre-eclampsia or small-for-gestational-age newborns [57]. Case–control studies give an OR of 2.02 (95% CI 1.60–2.55; 33 studies) for FVL and RPL and 1.81 to 2.07 for the prothrombin variant, with stronger associations in European studies, older women and losses after 10 weeks; protein C, protein S and antithrombin deficiencies showed no significant association [1]. RCOG concludes that the association with recurrent miscarriage is weak and more consistent with second-trimester miscarriage [2], and GeneReviews regards FVL heterozygosity as, at most, a weak contributor to recurrent or late loss, with a 2-fold greater risk of unexplained late fetal loss and a 4-fold greater risk in the second than the first trimester in a meta-analysis [21]. Heterozygosity for the prothrombin variant has, at most, a 2–3-fold relative risk [22]. MTHFR polymorphisms were historically classified as thrombophilia and are no longer considered in thrombotic risk assessment [1]. A recent systematic review cited by ASRM showed that thrombophilia prevalence in women with RPL is the same as in the general population [3].

2.10. Standardisation of cited variants

The variants in Table 2.3 were normalised on the MANE Select transcript using VariantValidator and compared with ClinVar; historical nomenclature is retained because it is used in guidelines and laboratory reports [58–61]. The FVL designation “1691G>A”, used by ESHRE, and the protein designation “R506Q” refer to the same c.1601G>A variant, as recorded in ClinVar itself [1, 59].

Table 2.3. Variants cited in the article, in HGVS and historical nomenclature [15, 43, 58–61]

The other KHDC3L variants described by Parry and colleagues were homozygous c.3G>T at the initiation codon in a Pakistani family with multiple consanguinity, and c.1A>G in compound heterozygosity with c.322_325del in an Asian patient; homozygous c.322_325del was found in a Tunisian patient and was absent from 208 Tunisian control chromosomes [15]. The second NLRP7 variant in the Cozette case, described as “Y318CfsX7”, corresponds in current notation to p.(Tyr318Cysfs*7), but the article does not publish its c. designation, so it cannot be normalised [43].

3. Clinical Spectrum and Manifestations by System

3.1. Natural history of pregnancy loss

Between 50% and 70% of all conceptions are lost when biochemical pregnancies are included, and 25–31% of clinically recognised pregnancies end in miscarriage, according to the compilation by Jauniaux and colleagues reproduced in the Oxford Desk Reference (Table 3.1) [5]. The meta-analysis in the Lancet “Miscarriage matters” series estimated the pooled miscarriage risk at 15.3% (95% CI 12.5–18.7) of recognised pregnancies, and ACOG gives 10% of clinically recognised pregnancies, with approximately 80% of losses in the first trimester and approximately half due to fetal chromosomal abnormalities [23, 30]. Differences reflect the denominator (all conceptions, recognised pregnancies or clinical pregnancies) and study period.

Table 3.1. Incidence of early pregnancy loss [5]

Miscarriage risk depends mainly on maternal age and number of previous losses. In a prospective registry study cited by RCOG, miscarriage risk was 13% at 12–19 years, 11% at 20–24, 12% at 25–29, 15% at 30–34, 25% at 35–39, 51% at 40–44 and 93% at 45 years or older [2]; ACOG gives 9–17% at 20–30 years, 20% at 35, 40% at 40 and 80% at 45 years [30]. Paternal age over 40 years also increases risk, to a lesser degree [2]. According to the systematic review cited by RCOG, the risk of another miscarriage was 11.3%, 17.0%, 28.0%, 39.6%, 47.2% and 63.9% with 0, 1, 2 or 3, 4, 5 and 6 previous miscarriages, respectively [2]. Primary and secondary RPL do not differ in prognosis, and sporadic miscarriage is more frequent in Black African or Caribbean women than White European women; consanguinity showed no association with recurrent miscarriage [2].

3.2. Clinical profile by genetic cause

Sporadic aneuploidy. Presentation is as a first-trimester miscarriage, sometimes a blighted ovum or missed miscarriage, with a peak in abnormalities at 8–10 weeks [42]. Aneuploidy in one miscarriage does not itself increase the risk of aneuploidy in the next pregnancy beyond the age-related risk [5, 33]. Anembryonic pregnancy and sporadic pregnancy loss of chromosomal cause are part of the differential diagnosis.

Parental structural rearrangements. The balanced carrier is phenotypically normal, and the family is often ascertained through repeated miscarriages, infertility (particularly in male Robertsonian translocation carriers) or the birth of a child with chromosomal imbalance [13, 14]. In a Dutch study of 278 carrier couples and 427 non-carrier couples referred after two or more miscarriages, followed for a mean 5.8 years, 49% of carriers and 30% of non-carriers had at least one further miscarriage (difference 19%; 95% CI 11–26), but 83% and 84%, respectively, had at least one healthy child [62]. By rearrangement type, subsequent miscarriage frequency was 54% in reciprocal translocations, 49% in inversions, 34% in Robertsonian translocations and 27% in other rearrangements [2]. In 550 carrier pregnancies in the Dutch study, there were 2 viable imbalances detected by prenatal diagnosis (0.4%) and 2 children born with an unbalanced karyotype (0.4%) [62]. In a Chinese series of 194 couples with reciprocal translocations selected for two or more adverse outcomes, the 592 pregnancies before preimplantation testing resulted in 496 miscarriages (83.8%), 36 pregnancies with congenital defects (6.1%) and 17 normal live births (2.9%), demonstrating the severity of reproductive history in a selected subgroup [63].

Triploidy. The vast majority are lost in the first trimester; survival into the third trimester is rare and ends in intrauterine or neonatal death [6]. Digynic triploidy more frequently survives into the second trimester, with severe IUGR, a disproportionately large head (sometimes with holoprosencephaly), small placenta, oligohydramnios and abnormal placental Doppler; diandric triploidy accounts for more than 90% of partial moles, with symmetrical IUGR and structural abnormalities in 82% (for example neural tube defects), raised maternal serum hCG in 80%, a large placenta and increased risk of pre-eclampsia [6]. Diploid/triploid mosaicism may survive and manifest as syndactyly (3rd and 4th fingers, 2nd and 3rd toes), clinodactyly, body asymmetry and streaky skin pigmentation [6].

Hydatidiform mole and gestational trophoblastic disease. Complete mole manifests as vaginal bleeding, nausea and vomiting, hyperemesis, risk of spontaneous miscarriage and hyperthyroidism [19]. Gestational trophoblastic disease (GTD) includes complete and partial mole, placental site trophoblastic tumour and choriocarcinoma [6]. In the United Kingdom, persistent trophoblastic disease follows 15% of complete moles and 0.5–1% of partial moles, and choriocarcinoma occurs in up to 3% of complete moles and approximately 0.1% of partial moles; incidence after term pregnancy is 1/40 000 to 1/50 000 [6]. The risk of another mole is approximately 1% after one mole and 15–18% after two according to the Oxford Desk Reference, or approximately 1.5% and 25% according to the introduction by Cozette and colleagues [6, 43].

Recurrent mole due to biallelic maternal variants. Women with biallelic NLRP7 variants have repeated molar pregnancies, miscarriages, stillbirths and IUGR, and normal spontaneous pregnancies are rare: 3 of 131 published patients up to 2015, associated with certain missense variants with mild functional consequences [8, 50]. In the prospective northern Indian cohort (2005–2022), 22 of 23 women with recurrent mole and no previous live birth (95.6%) had biallelic pathogenic or likely pathogenic variants (20 in NLRP7, 1 in KHDC3L, 1 in TOP6BL), and only one of the 22 had a spontaneous live birth [26]. By 2014, no live births had been described in patients with two defective KHDC3L alleles [9].

Gestational trophoblastic neoplasia risk in recurrent mole: conflicting data. In the same Indian cohort, 10 of the 20 women with biallelic NLRP7 (50%) developed gestational trophoblastic neoplasia (GTN), mostly low risk, approximately 2–3 times the rate observed after sporadic mole at similar ages, and 3 had recurrent GTN [26]. A 2026 review concludes that biallelic NLRP7 confers a substantial lifetime risk of GTN, including choriocarcinoma, and proposes genotype-stratified oncological surveillance [49]. These conclusions contradict two earlier statements: that of Cozette and colleagues, according to which “there is no risk of malignant degeneration in recurrent forms of complete mole” (a statement also contradicting their own assertion that biparental moles have the same prognosis as diandric moles) [43], and that in the GeneGuidance KHDC3L record, which, citing Nguyen and Slim (2014), states that these patients would at least not have a greater risk of choriocarcinoma [9, 64]. Prospective cohort data (n=20 with biallelic NLRP7, one centre, one population) are the best available evidence and justify hCG surveillance after each pregnancy, but the 50% estimate comes from a small sample and should not be treated as a validated lifetime risk in other populations [26, 49].

Maternal-effect genes with MLID. Mothers with biallelic variants may have children with an imprinting disorder, children with MLID, healthy children, pregnancy losses, molar pregnancy or apparent infertility; MLID in more than one child strongly suggests a biallelic maternal variant [7].

X-linked dominant disorders and monogenic lethality. Loss of male fetuses in a woman with cutaneous or dental signs of incontinentia pigmenti, focal dermal hypoplasia or orofaciodigital syndrome guides diagnosis [5, 16]. In fetal akinesia sequence, recurrent affected pregnancies manifest as reduced fetal movements, contractures and polyhydramnios on ultrasound [55].

3.3. Long-term consequences and associated manifestations

Large cohort studies associate RPL with a greater late risk of cardiovascular disease, stroke, diabetes, autoimmune disease and mental illness, with 39-year follow-up data cited by ASRM [3]. Miscarriage, particularly recurrent miscarriage, is also a marker of preterm delivery, fetal growth restriction (FGR), placental abruption and stillbirth in future pregnancies, and of cardiovascular disease and VTE in the long term; women with miscarriage have more anxiety, depression, post-traumatic stress disorder and suicide [23]. In the United Kingdom, the cost of miscarriage was estimated at 471 million pounds annually [23]. These data are observational associations and do not establish that the genetic cause of each case carries the same risk.

4. Clinical Recognition and Warning Signs

RPL is a common condition in which the couple's genetic cause is in the minority; most repeated losses result from successive sporadic aneuploidies, more frequent with age [3, 33]. Suspicion of a parental or monogenic genetic cause should increase in the contexts in Table 4.1. ESHRE recommends that medical and family history guide investigation (good practice point, GPP) [1]. A three-generation pedigree should record miscarriages, stillbirths, neonatal deaths, unexplained intellectual disability and congenital anomalies [5, 44], and, when there have been molar pregnancies, ask about infertility, multiple miscarriages, moles and children with imprinting disorders in female relatives [7].

Table 4.1. Contexts suggesting a specific genetic cause in RPL

Clinical warning signs requiring urgent assessment beyond genetics include vaginal bleeding, hyperemesis or signs of hyperthyroidism in early pregnancy, suggesting mole [19]; hCG failing to fall to undetectable levels after evacuation of a mole, indicating persistent disease that may require chemotherapy [6, 8]; and a history of thrombosis in a woman with losses, requiring investigation for APS [1, 3]. There is no neonatal screening relevant to RPL.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and guideline recommendations

RPL diagnosis is clinical and based on the number of confirmed losses; genetic aetiological diagnosis depends on POC analysis, parental karyotyping and, in selected situations, molecular testing. The five current guidelines differ in the loss threshold, timing of POC analysis, indications for parental karyotyping and position on preimplantation genetic testing (Table 5.1). They agree against routine hereditary thrombophilia screening and against treating hereditary thrombophilia with anticoagulants to prevent pregnancy loss. ESHRE 2022 remains the current version (the society's website lists no later update in October 2026); ASRM 2026 replaces the 2012 document; RCOG 2023 replaces the 2011 version and searched the literature up to November 2021, before the ALIFE2 trial; ACOG has no current document specific to RPL, and its position comes from Practice Bulletin 200 on early pregnancy loss, published in 2018 and reaffirmed in 2025 [1–4, 24, 30].

Table 5.1. Comparison of current guidelines on genetic and thrombophilia assessment in RPL

Sources for Table 5.1: [1–4, 30].

SOGC is the only one of these societies recommending consideration of preimplantation genetic testing in reciprocal or Robertsonian translocation carriers to shorten time to live birth and reduce losses, with a conditional recommendation based on low-quality evidence; ESHRE and RCOG conclude from the same observational studies that PGT-SR improves neither live birth rate nor time to pregnancy [1, 2, 4]. A commentary published in 2026 criticises SOGC from the opposite perspective, for underusing CMA and POC sequencing [65].

5.2. Genetic analysis of the products of conception

POC analysis provides an explanation for the loss and may guide the need for further investigation, but has not been shown to change prognosis in terms of live births, and an aneuploid result does not exclude other causes [1]. The stepwise strategy proposed by several authors and adopted by ASRM consists of analysing tissue from the second loss and investigating maternal factors (acquired thrombophilia, thyroid, uterus) only if the result is euploid; this approach increases the proportion of couples with an explanation and reduces costs, and combining POC chromosomal analysis with the usual clinical assessment identifies a probable or definitive cause in more than 90% of cases in the cited series [1–3]. ASRM changed its position in 2026 based on cost-effectiveness data, patient satisfaction and emotional benefit, because analysis reduces feelings of guilt and self-blame, and allows analysis at the first miscarriage for explanatory purposes, recalling that a single early euploid miscarriage does not increase the risk of a second loss and does not justify reflex investigation [3].

Table 5.2. POC analysis techniques: capabilities and limitations [1–3, 5]

In the meta-analysis by Dhillon and colleagues, concordance between G-banded karyotyping and CMA in miscarriage was 86.0% (95% CI 77.0–96.0); CMA detected 13% (95% CI 8.0–21.0) additional abnormalities, full karyotyping 3% (95% CI 1.0–10.0) additional abnormalities such as balanced translocations, and variants of uncertain significance (VUS) occurred in 2% (95% CI 1.0–10.0) [5]. No technique detects all abnormalities, and the most complete results may require combined techniques [3]. Maternal cell contamination limits interpretation of a 46,XX result; it depends on the sampling technique and decreases with careful separation of villi and gentle washing of tissue with saline; molecular fingerprinting with polymorphic markers compares maternal DNA with miscarriage DNA [2, 3]. RCOG advises prompt dispatch to the laboratory and storage of part of the tissue at −80 °C for FISH or molecular analysis [2]. Home tissue collection after medical management of miscarriage is possible and should be discussed with patients who do not opt for surgical evacuation [3].

5.3. Cell-free DNA in maternal plasma after miscarriage

When tissue is unavailable, cell-free DNA (cfDNA) in maternal plasma may serve as screening for miscarriage aneuploidy. In a meta-analysis of 7 studies with 887 women with miscarriage before 20 weeks, using tissue cytogenetics as the reference, sensitivity and specificity were 100% (95% CI 81.5–100) and 100% (99.1–100) for trisomy 21, 100% (54.1–100) and 100% (99.0–100) for trisomy 18, 88.9% (51.8–99.7) and 100% (99.1–100) for trisomy 13, 75.8% (65.7–84.2) and 99.4% (97.9–99.9) for other autosomal trisomies and 60.0% (14.7–94.7) and 100% (97.4–100) for CNV, with test failure in 7.3% (5.7–9.2) [66]. In another meta-analysis of genome-wide cfDNA in losses before 22 weeks (8 series, 552 miscarriages with informative results by both methods), pooled sensitivity was 78% (71–83), specificity 91% (86–95) and concordance 84% (81–87); with positive cfDNA, the probability of aneuploidy was 93%, and with negative cfDNA still 28% [67]. An Italian retrospective study from 2022–2025 compared cfDNA with tissue CMA in miscarriages between 7 and 14 weeks [68]. cfDNA does not replace tissue analysis: it is a screening test, its sensitivity for rare trisomies and CNV is lower and a negative result does not exclude aneuploidy [66, 67].

5.4. Parental karyotyping and low-coverage genomic sequencing

An abnormal parental karyotype is found in approximately 1.9% of parents referred for recurrent miscarriage: in the audit of four United Kingdom centres (the Wessex series by Barber and colleagues), 406 balanced rearrangements in 20,432 parents, with only 4 unbalanced translocations subsequently detected through prenatal diagnosis, led RCOG to regard universal parental screening as not cost-effective [1, 2, 5]. In a database cited by RCOG, a translocation was found in 2.2% of parents after one miscarriage, 4.8% after two and 5.7% after three; in other series, in 3.5% of 795 couples with two or more losses [1, 2]. The Québec study by De Braekeleer and Dao (more than 22,000 couples) estimated 4.7% versus 0.5% in the reference population [5]. Carrier probability is very low when the woman is 39 years or older, has fewer than three losses and a negative family history, according to a nested case–control study of 279 carrier couples and 428 controls [1]. Karyotyping does not predict whether the next pregnancy will be unbalanced, and cumulative live birth rates are good even in carriers: 64% in one series, and 63.0% in carriers versus 78.7% in couples with a normal karyotype in another, which did not state how many couples discontinued [1].

ASRM records the explicit divergence: ASRM 2012 and ACOG recommended routine parental karyotyping, whereas ESHRE and RCOG limit it to individual assessment or an unbalanced rearrangement in POC [3]. ASRM 2026 recommends offering investigation for parental balanced structural rearrangements when POC analysis shows an unbalanced rearrangement or when chromosomal analysis of miscarriages is unavailable, citing against routine karyotyping the low carrier probability with fewer than three miscarriages, negative family history and maternal age over 39 years, reassuring cumulative live birth rates without PGT, costs and psychological impact [3]. G-banded karyotyping remains the first available test but misses small rearrangements or those with similar banding patterns [3]. In low-coverage genomic sequencing of 1090 Chinese couples with recurrent miscarriage, all previously karyotyped, results were obtained in 1077 (98.8%) and abnormalities in 126 couples (11.7%), 50 of whom (39.7%) had a previously normal karyotype, through 8 additional balanced translocations and 42 inversions; yield per couple was 11.7% versus 8.0% with karyotyping, and in pregnancy follow-up carriers of the additional abnormalities had miscarriage or fetal abnormality in 5 of 10, with a relative risk of 2.2 (95% CI 1.1–4.6) [37]. Genomic array does not detect balanced translocations: a normal array in an at-risk relative does not indicate whether they inherited the translocation [13].

5.5. Investigation of recurrent hydatidiform mole

Each mole requires aspiration, histopathological examination with p57 immunohistochemistry (which may be discordant in NLRP7-associated moles) and genetic tissue analysis, followed by serial hCG measurement until undetectable levels [8]. Molar tissue genotyping with comparison with parental DNA is the triage step: a biparental diploid mole directs investigation towards NLRP7 and KHDC3L in the woman, whereas an androgenetic or triploid mole makes this hypothesis unlikely [8, 25]. The algorithm proposed by Nguyen and Slim consists of first investigating NLRP7, present in 48–80% of women with two or more moles, then KHDC3L [9]. The 2022 expert consensus recommends genetic testing and counselling for all women with recurrent mole, describes classification of recessive variants according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, and records variants in Infevers [36]. Women with two or more biparental diploid complete moles may be counselled as those with confirmed variants, even without an identified variant [9]. MEI1, TOP6BL and PADI6 complete the panel [10, 26, 43]. Variant phase must be established: two variants on the same allele (in cis) do not explain a recessive disorder, and testing the woman's parents is necessary to establish compound heterozygosity, as illustrated by the clinical case in section 10 [43].

In cases with suspected MLID in offspring, testing starts with the child, using a test targeted to the imprinting disorder and, for MLID, a methylation-sensitive method (MS-MLPA, pyrosequencing, long-read sequencing, methylation arrays) assessing all clinically associated loci and sensitive to mosaicism; in the mother, diagnosis requires biallelic pathogenic or likely pathogenic variants in a gene in Table 2.2, and biallelic VUS or a pathogenic variant with a VUS neither establish nor exclude diagnosis [7].

5.6. Exome and genome sequencing in euploid losses

ESHRE considers NGS, SNP-array and exome or genome sequencing insufficiently studied in RPL and potentially useful in the future [1]. Available data come from very different populations and selection criteria, and yields cannot be compared (Table 5.3). In fetuses with structural anomalies, trio exome sequencing after uninformative karyotyping or CMA was diagnostic in 10% of 234 trios in New York [39], and the PAGE study (England and Scotland, 610 fetuses, virtual panel of 1628 genes) found a diagnostic variant in 8.5% (95% CI 6.4–11.0), higher in multisystem (15.4%) and skeletal (15.4%) anomalies and lower in isolated increased nuchal translucency (3.2%) [40]. In 2020, ACMG published a points-to-consider document on fetal exome sequencing in prenatal diagnosis [69].

Table 5.3. Diagnostic yield of exome and genome sequencing in pregnancy losses

In the North American genome sequencing series, the 25 families with an inherited variant included 2 with parental germline mosaicism, 7 with a heterozygous variant transmitted by an affected or asymptomatic parent, 5 hemizygous and 11 biallelic, and 4 additional families (3.4%) had ultrarare biallelic variants in genes without known human disease, in pathways of haematopoiesis, cardiovascular development, inflammation and fluid homeostasis [72]. The authors of that abstract estimate that RPL affects approximately 5% of women, above guideline estimates (1–2% of couples in ESHRE; approximately 1% of women with three or more miscarriages in RCOG), which is not supported by the other sources consulted [2, 24, 72]. In the Saudi series, lethal biallelic forms of usually dominant disorders and 46 genes without an OMIM phenotype show that exome interpretation in losses requires specific databases such as Human Intolerome [41, 73]. When fetal monogenic lethality is suspected, the Oxford Desk Reference recommends CMA, panel, exome or genome sequencing, fetal and parental DNA banking and full autopsy (neuropathology, muscle histology, electron microscopy), and, in fetal akinesia, testing for maternal antibodies against fetal and adult acetylcholine receptors and MuSK, exclusion of myotonic dystrophy and spinal muscular atrophy and, if necessary, skin karyotyping for diploid/triploid mosaicism [55]. Autopsy allows fluids and tissues to be collected for biochemical confirmation when an inborn error of metabolism is suspected (“metabolic autopsy”) [56].

5.7. Tests that should not be performed routinely

Hereditary thrombophilias. FVL testing has 98.8% sensitivity and 99.3% specificity, and prothrombin variant testing 98.3% and 99.6%, but a positive result is not associated with a better outcome and exposes patients to harm (anticoagulation risks, costs, treatment after a false positive) [1]. ESHRE suggests not screening for hereditary thrombophilia in RPL except in research or women with additional risk factors, such as relatives with hereditary thrombophilia or previous VTE; antithrombin, protein C and particularly protein S levels vary during pregnancy and testing should be delayed until at least 6 weeks after the loss, whereas DNA tests for FVL and prothrombin can be interpreted at any time [1]. RCOG allows FVL, prothrombin and protein S testing to be offered to women with second-trimester miscarriage, ideally in research, with prior counselling on implications for themselves and relatives; protein S should be measured at least 6 weeks postpartum without hormonal medication, and protein C, antithrombin and MTHFR should not be tested [2]. ASRM, SOGC and ACOG do not recommend screening [3, 4, 30], and GeneReviews includes unexplained pregnancy loss among situations where FVL testing is not recommended [21, 22]. The 2023 American Society of Hematology (ASH) guideline on thrombophilia testing, with 23 recommendations of almost invariably very low certainty, suggests testing pregnant women with a family history of high-risk thrombophilia, among other VTE scenarios, and does not include RPL among indications [74]. The historical 2001 ACMG recommendation, according to which FVL testing “may be considered” in women with recurrent pregnancy loss, has been superseded [12, 21].

MTHFR, HLA and cytokines. MTHFR c.665C>T (historical C677T) showed an association with RPL in some reviews but not others, and should not be tested [1–3]. HLA typing is not recommended, with the conditional exception of class II HLA alleles (HLA-DRB1*15:01, HLA-DRB1*07, HLA-DQB1*05:01/05:02) in Scandinavian women with secondary RPL after the birth of a boy, solely for prognostic purposes; cytokine polymorphisms should not be tested (strong) [1].

Antiphospholipid antibodies. These are not a genetic test, but form part of assessment in all guidelines: ESHRE recommends lupus anticoagulant and IgG and IgM anticardiolipin antibodies after two losses (strong), and anti-β2-glycoprotein I may be considered [1]; RCOG requires two positive tests at least 12 weeks apart and at least 6 weeks after miscarriage, for lupus anticoagulant (preferably by dilute Russell viper venom time with platelet neutralisation) or medium- or high-titre IgG or IgM anticardiolipin (above 40 GPL/MPL or the 99th percentile) [2].

5.8. Genetic assessment algorithm

Table 5.4. Practical genetic assessment algorithm in RPL (guideline synthesis; points of divergence indicated)

5.9. Test limitations and report content

A normal result does not exclude a genetic cause. Array does not detect balanced rearrangements or, for aCGH, triploidy, and does not detect low-level mosaicism; karyotyping does not detect submicroscopic imbalances; cfDNA is screening; and exome and genome sequencing in euploid losses still have neither an established diagnostic panel nor comparable yield between studies [1, 3, 5, 38, 67]. The proportion of detectable variants in a gene does not equate to the clinical sensitivity of the test: for example, biallelic NLRP7 and KHDC3L variants account for 50–80% of patients with recurrent mole, but absence of variants does not exclude another genetic cause, particularly if moles are biparental diploid [9, 25]. A molecular test report should specify the gene, transcript with version, HGVS designation, zygosity, phase when relevant and ACMG/AMP classification; cytogenetic reports should give the karyotype with breakpoint definitions, necessary for risk calculation and testing relatives [36, 44]. VUS in maternal-effect genes should not guide reproductive decisions, and segregation testing in the parents is necessary to establish phase [7, 43].

Prenatal diagnosis and preimplantation genetic testing in rearrangement carriers and women with maternal-effect gene variants are discussed in section 8.

6. Differential Diagnosis

Differential diagnosis of genetically caused RPL has two levels: among genetic causes themselves, with very different recurrence risks and reproductive options, and between genetic causes and acquired or anatomical maternal causes, which coexist in the same couple. An aneuploid miscarriage does not exclude other causes, and a translocation carrier couple may also have aneuploid miscarriages independent of the rearrangement [1].

Table 6.1. Differential diagnosis of RPL causes

Hereditary thrombophilias. Hereditary thrombophilias were considered a cause of RPL for decades, but the association with first-trimester loss is weak and the prevalence of these variants in women with RPL equals that in the general population [2, 3]. FVL heterozygosity is present in 3–8% of the population in the USA and Europe, so a positive result in a woman with RPL is often coincidental [17]. RCOG distinguishes second-trimester miscarriage, in which the association with FVL, prothrombin and protein S deficiency is more consistent and testing may be offered, ideally in a research setting [2].

Antiphospholipid syndrome. This is the only thrombophilic condition consistently associated with pregnancy loss, and it is acquired [30]. The Miyakis classification criteria include three or more consecutive unexplained miscarriages before 10 weeks, with exclusion of parental and maternal chromosomal causes, making genetic assessment part of APS diagnosis itself [1]. APS has evidence-based treatment, unlike hereditary thrombophilia, and is therefore the main differential diagnosis that must not be omitted (section 7.5).

Sporadic and biparental mole. Two moles in the same woman may result from two independent sporadic events, particularly in populations with a high mole incidence; tissue genotype distinguishes androgenetic or dispermic triploid moles, frequent in patients without variants, from biparental diploid moles, which characterise patients with biallelic variants [25]. Patients without variants are mainly non-familial, have fewer losses and more live births, suggesting milder or multifactorial susceptibility [25].

Paternal factors. Paternal age over 40 years increases miscarriage risk, and ASRM includes sperm DNA fragmentation among tests to consider in certain circumstances; a 2026 review emphasises growing recognition of paternal factors [2, 3, 75].

7. Treatments and Risk Management Strategies

7.1. Principles

No treatment corrects genetic causes of RPL. Sporadic aneuploidy, parental rearrangements and maternal-effect gene variants have no pharmacological treatment; intervention consists of genetic counselling, prognostic information and choosing between reproductive options: further natural conception with or without prenatal diagnosis, in vitro fertilisation (IVF) with preimplantation genetic testing, donor gametes or adoption [1–3]. ESHRE recommends, as good practice, that all couples with an abnormal fetal or parental karyotype receive genetic counselling and information on options, with advantages and disadvantages [1], and ASRM includes genetic counselling for a known genetic cause (parental translocation) or high-risk family history within standard care [3]. Preconception optimisation and psychological support form part of standard care in all guidelines [3, 4, 76]. RCOG recommends a body mass index between 19 and 25 kg/m², smoking cessation and caffeine consumption below 200 mg/day [2].

When POC analysis shows aneuploidy, counselling focuses on age-related risk and prognosis: an aneuploid miscarriage is associated with a greater probability of subsequent live birth than a euploid miscarriage (68% versus 41% subsequent live births in one series) [2, 5]. Empirical treatments (anticoagulants, ASA, immunotherapies) are not indicated in unexplained RPL [1–3].

7.2. Preimplantation genetic testing for structural rearrangements (PGT-SR)

PGT-SR (formerly preimplantation genetic diagnosis, PGD) requires IVF, embryo biopsy and analysis of segments involved in the rearrangement by FISH, aCGH or NGS, mainly using blastocyst biopsy (days 5 to 7) or, less frequently, blastomere biopsy on day 3 [77]. FISH is acceptable for rearrangements with small or subtelomeric fragments difficult to detect by other methods (for example below 10 Mb), using at least the probes needed to detect all expected imbalances (three informative probes, two distal and one proximal or vice versa; in Robertsonian translocations, any locus on the long arms of the acrocentrics involved); FISH distinguishes neither a normal from a balanced embryo nor mosaicism in a single-cell biopsy, and detection of small segments by aCGH depends on platform resolution [77]. Before the cycle, the couple should have karyotypes, results from previous unbalanced pregnancies, a counselling report covering the method, benefits and limitations, and informed consent, including the risk of viable unbalanced offspring through detection failure and the risks of miscarriage, stillbirth, unbalanced or mosaic offspring and unrelated imbalance [77]. PGT-SR does not help carriers of homologous Robertsonian translocations such as rob(21q21q), because virtually all conceptions are unbalanced, and may not detect UPD [14]. In reciprocal translocation carriers undergoing PGT-SR, ASRM recommends discussing increased offspring UPD risk, illustrated by Silver-Russell syndrome due to maternal UPD7 in a family with t(7;13), and the potentially higher additional aneuploidy rate in female carriers [3].

Evidence on efficacy is observational. Without ART, translocation carrier couples have live birth rates up to 70–71% and miscarriage rates as low as 29–30% [3]. A review without randomised trials, including FISH studies, showed no live birth rate improvement with PGT-SR [1]. In a Japanese study, live birth rate in the first pregnancy was 37.8% after PGT-SR and 53.8% in the first natural pregnancy (OR 0.52; 95% CI 0.22–1.23); PGT-SR reduced miscarriages, but cumulative live birth rate (OR 1.10; 95% CI 0.45–2.70) and time to pregnancy (12.4 versus 11.4 months) were similar [1]. In a case–control study of 89 couples cited by RCOG (52 with natural conception and 37 with IVF or intracytoplasmic sperm injection, ICSI, with PGD), cumulative live birth rates were 67.6% versus 65.4%, with similar time to pregnancy, fewer miscarriages with PGD and a cost of 7956 US dollars per patient [2]. In a Chinese series of 194 couples with reciprocal translocations and two or more adverse outcomes, 265 PGT-SR cycles resulted in 118 clinical pregnancies, with 11.0% miscarriages, 85.6% normal live births and 3.4% children with defects, mostly mild; the live birth rate was 56% per euploid embryo transfer and 38% per initiated cycle [3, 63]. This study compares before and after, without a natural conception group, and selects couples with a very adverse history [63]. In a series of 1942 PGT-SR cycles, on average at least 4.5 blastocysts were needed for a good probability of a euploid embryo, and the euploidy rate was 17–22% depending on maternal age [3]. After counselling, 76.9% (206/268) of translocation carrier couples chose PGT-SR in one study, whereas in a Canadian series natural conception was chosen twice as often as PGT-SR [1].

Recommendations differ (Table 5.1). ESHRE requires informing couples that PGT-SR may reduce miscarriages but improves neither live birth rate nor time to pregnancy, and recalls that PGT is not permitted in some countries [1]; RCOG states that PGD should not be routinely offered and presents further natural conception, PGT-SR and gamete donation as options [2]; ASRM states that IVF with PGT-SR and donor gametes may be offered, that efficacy versus expectant management is not established because prospective trials are lacking, and that advanced maternal age and low ovarian reserve reduce euploid embryo probability and may require several cycles [3]; SOGC suggests considering PGT to shorten time to live birth and reduce losses, with a conditional recommendation and low-quality evidence [4]. The Oxford Desk Reference suggests considering PGD in couples with non-homologous Robertsonian translocations after three or more miscarriages, or in a male carrier with infertility and oligospermia, and observes that in practice it is more sought by women with translocations involving chromosome 21 [14]. Most couples referred for PGD are fertile, and counselling should compare success probability per cycle with that of natural conception [78].

7.3. Preimplantation genetic testing for aneuploidy (PGT-A)

PGT-A has been proposed in unexplained RPL on the grounds that most losses are due to aneuploidy. Evidence has not demonstrated benefit versus expectant management, and no published randomised trial compares IVF with PGT-A against expectant management in women with RPL [1, 3]. The PubMed and ClinicalTrials.gov search in October 2026 did not identify such a trial, which does not prove none exists [79, 80].

In a retrospective intention-to-treat study, live birth rates per attempt were 32% with PGT-A and 34% with expectant management, and median time to pregnancy was 6.5 and 3.0 months, respectively; benefit was limited to women over 40 years reaching a euploid transfer, and IVF with PGT-A was not cost-effective [1, 3]. In the North American SART-CORS registry (12,631 frozen embryo transfer cycles in women with three or more miscarriages; the ASRM text prints the number as “1,2631”), the adjusted live birth OR with PGT-A was 1.31 (95% CI 1.12–1.52) below 35 years, 1.45 (1.21–1.75) at 35–37, 1.89 (1.56–2.29) at 38–40, 2.62 (1.94–3.53) at 41–42 and 3.80 (2.52–5.72) above 42 years, without a significant reduction in clinical miscarriage in any age group; controls were IVF cycles without PGT-A in infertile women, rather than expectant management [3]. A Japanese study (aCGH; 41 women with RPL with PGT-A and 38 without) reduced biochemical loss and increased live births per transfer, but not live births per patient (26.8% versus 21.1%) [1]. The 2025 meta-analysis found lower clinical loss (OR 0.42; 95% CI 0.27–0.67) and more live births per transfer (OR 2.17; 1.77–2.65) and per patient (OR 1.85; 1.18–2.91) with PGT-A, with low-quality evidence; euploid transfers in women with and without RPL had similar clinical loss (OR 1.10; 0.57–2.13) and live births (OR 1.04; 0.74–1.44), which does not support the hypothesis of a “less selective” endometrium [81]. That meta-analysis did not analyse by oocyte retrieval with intention to treat and did not consider costs, time or cycles without transfer; miscarriage still occurs in 10–20% of pregnancies after PGT-A [3].

ASRM concludes that PGT-A has not been shown to reduce miscarriage or increase live births versus expectant management in RPL, and that in women over 40 years with proven aneuploid miscarriage it is reasonable to discuss PGT-A through shared decision-making to reduce aneuploid miscarriages, explaining that it neither shortens time to pregnancy nor increases live births [3]. RCOG considers data insufficient for routine use, with potential cost and risk [2]; ESHRE makes no favourable recommendation in RPL and, in its 2023 good practice recommendations on add-ons, does not recommend PGT-A for routine clinical use, citing interlaboratory discrepancies in mosaicism diagnosis, potential discarding of viable embryos and signals of more low birth weight, prematurity and hypertensive disease in newborns [1, 82]. ASRM and SART concluded in 2024 that the value of PGT-A as routine screening in all IVF is not established [83]. A 2026 review is more favourable and considers PGT-A beneficial in older patients with recurrent aneuploid losses [75]. Non-invasive PGT-A (in culture medium or the blastocoel) is in development and unsuitable for clinical practice [82].

7.4. Recurrent hydatidiform mole: oocyte donation and surveillance

There is no treatment correcting the oocyte defect in women with biallelic NLRP7 or KHDC3L variants, and preimplantation genetic testing of their own embryos is not useful because all oocytes are affected [7–9]. Oocyte donation is the documented route to a normal pregnancy: 3 live births in 2 women in a 2015 series, one term birth in the Cozette and colleagues case, 3 live births in 4 women undergoing IVF with donated oocytes in the Indian cohort, and a total of 4 published normal pregnancies following oocyte donation up to 2020 [26, 43, 50]. The 2026 review regards oocyte donation as the standard reproductive option [49]. A woman who had a child through oocyte donation subsequently had another complete mole after spontaneous conception, so spontaneous conception retains the risk even after a donor-oocyte child [8, 43]. Live births with own oocytes are rare and associated with specific missense variants, and should not underpin routine counselling [49, 50].

Each molar pregnancy requires aspiration, histopathology, genetic tissue analysis and serial hCG measurement to undetectable levels; persistent disease is treated with chemotherapy, with methotrexate first line, and in the United Kingdom chemotherapy is adjusted by the International Federation of Gynecology and Obstetrics (FIGO) score, with cure in more than 98% of registered cases [6, 8]. In low-risk gestational trophoblastic neoplasia, FIGO (2025) recommends the 8-day regimen of methotrexate 50 mg intramuscularly on days 1, 3, 5 and 7 with oral folinic acid 15 mg 24 h after each dose (days 2, 4, 6 and 8), repeated every 2 weeks, and the EOTTD-ESGO guideline (2025) accepts 1 mg/kg or a fixed 50 mg in the same regimen; the alternative is methotrexate 0.4 mg/kg per day, intravenously or intramuscularly, for 5 days, not exceeding 25 mg/day, every 2 weeks [84, 85]. In subsequent pregnancies, early ultrasound (approximately 8 weeks) and hCG measurement after each pregnancy are recommended [8]. Given the GTN risk described in the Indian cohort, hCG surveillance after each pregnancy in women with biallelic variants should not be waived based on Cozette and colleagues' assertion that recurrent forms carry no malignant risk [26, 43, 49]. Danish guidance and a German, Austrian and Swiss S2k guideline on gestational trophoblastic disease exist and are cited by GeneGuidance [8, 9].

7.5. Hereditary thrombophilia and antiphospholipid syndrome

Hereditary thrombophilia. ESHRE suggests not using antithrombotic prophylaxis in women with hereditary thrombophilia and RPL, except in research or when indicated to prevent VTE [1]. The ALIFE2 trial randomised 326 women aged 18 to 42 years with two or more losses and confirmed hereditary thrombophilia (United Kingdom, Netherlands, USA, Belgium and Slovenia; 2012–2021) to low-dose low-molecular-weight heparin (LMWH), started by 7 weeks and continued until the end of pregnancy, plus standard care, or standard care alone; live births were 72% (116/162) versus 71% (112/158), with an adjusted OR of 1.08 (95% CI 0.65–1.78) and an absolute difference of 0.7% (−9.2 to 10.6), and adverse events (bleeding, thrombocytopenia, skin reactions) occurred in 24% versus 23% [27]. The authors concluded that LMWH should not be used and hereditary thrombophilia should not be screened for in RPL [27]. The published abstract does not specify the exact LMWH drug or dose. ASRM considers, based on high-quality evidence, that anticoagulants are not recommended in RPL with hereditary thrombophilia or in unexplained RPL [3]. RCOG, whose search ended before ALIFE2, allows individual decisions based on thrombotic risk or previous placental thrombosis, and cites a trial in which women with one late loss after 10 weeks and FVL, the prothrombin variant or protein S deficiency had 86% live births with enoxaparin versus 29% with low-dose aspirin (OR 15.5; 95% CI 7–34), not confirmed by a later trial that showed no difference between subgroups with and without thrombophilia [2]. In pregnancy, warfarin is teratogenic and prophylactic heparin is preferred in women at high thrombotic risk; FVL homozygotes have an approximately 80-fold relative risk of VTE and heterozygotes a 4–8-fold risk [12]. ACOG Practice Bulletin No. 197 (2018), on hereditary thrombophilias in pregnancy, recognises that the evidence to guide screening for and management of these conditions in pregnancy is limited and defines candidates for assessment and prophylaxis by VTE risk [86]. Thromboprophylaxis for VTE risk follows haematological and obstetric guidelines [3, 74].

Antiphospholipid syndrome. In APS with three or more losses, ESHRE suggests low-dose ASA (75–100 mg/day) from before conception and prophylactic heparin (unfractionated heparin or LMWH) from a positive pregnancy test (conditional); in APS with two losses, this treatment is limited to research [1]. In the Cochrane meta-analysis of 11 trials (1672 women), heparin with ASA versus ASA alone increased live births (relative risk, RR, 1.27; 95% CI 1.09–1.49; 5 studies; n=1295) [1]. RCOG recommends ASA with heparin from a positive test until at least 34 weeks [2], and SOGC recommends low-dose ASA from before conception and prophylactic heparin when intrauterine pregnancy is confirmed (strong, high) [4]. The prophylactic LMWH dose in pregnancy is based on booking weight, according to RCOG (Green-top Guideline 37a), given subcutaneously once daily: enoxaparin 20 mg (< 50 kg), 40 mg (50–90 kg), 60 mg (91–130 kg) and 80 mg (131–170 kg), the last two divisible into two doses, and 0.6 mg/kg/day above 170 kg; dalteparin 2,500, 5,000, 7,500 and 10,000 U/day in the same weight bands and 75 U/kg/day above 170 kg; tinzaparin 75 U/kg/day (3,500, 4,500, 7,000 and 9,000 U/day in the same weight bands); the high prophylactic dose, at 50–90 kg, is enoxaparin 40 mg, dalteparin 5,000 U or tinzaparin 4,500 U every 12 hours, and the guideline defines no maximum dose [87]. For treatment of acute VTE in pregnancy, ASH 2018 recommends LMWH over unfractionated heparin (strong), once or twice daily, without routine anti-Xa monitoring [88]; the therapeutic doses on the enoxaparin label (Lovenox®) are 1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg once daily, with no maximum dose defined on the label for VTE, and use in pregnancy rests on the guidelines rather than on a specific label indication [88, 89].

7.6. Other non-genetic interventions mentioned in guidelines

These interventions do not act on genetic causes, but form part of management of women with RPL and euploid POC or no identified cause, and guidelines differ on them.

Table 7.1. Drugs mentioned in RPL guidelines: indication, dose and society positions

In unexplained RPL, ESHRE advises against heparin and ASA (strong), granulocyte colony-stimulating factor (strong) and sperm selection through hyaluronic acid binding (conditional) [1, 24]. In an uncontrolled series cited by ESHRE, L-methylfolate with vitamins B6 and B12 normalised homocysteine in 76% of women with MTHFR variants or hyperhomocysteinaemia, and 22 of 25 women became pregnant after normalisation, with 20 live births (4 preterm and 2 with mild FGR); these data do not support a recommendation [1]. ASRM classifies IVIg, intravenous lipid emulsions and prednisone as ineffective or without evidence, and correction of the uterine cavity, chronic endometritis treatment, metformin, IVF with PGT-A or PGT-SR and donor gametes as of possible benefit [3]. The clearest divergence between societies in this area is IVIg, which ESHRE conditionally allows in four or more losses and ASRM regards as ineffective [3, 24].

7.7. Regulatory framework

The sources consulted identify no medicine with an indication approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for RPL; individual drug labels were not searched because none has a specific indication in this entity. Use of ASA, heparin, progesterone and IVIg in this setting is therefore off-label and based on guidelines. Preimplantation genetic testing is a procedure regulated differently between countries (Table 7.2).

Table 7.2. Regulatory framework for interventions in genetically caused RPL

HFEA permits PGD for Robertsonian translocations, reciprocal translocations and other rearrangements (inversions, deletions), and RCOG refers to its website (www.hfea.gov.uk) for current information on PGT-SR and PGT-A in the United Kingdom [2, 78]. Data on access to PGT in Portugal and Brazil are not included in the sources consulted.

7.8. Trials and comparative studies

Table 7.3. Main trials and comparative studies of RPL interventions

These studies do not allow indirect comparisons: populations, RPL definitions, comparators (expectant management, IVF without testing, placebo) and outcomes (per transfer, cycle or patient) differ. Relative reductions must be read alongside the absolute rate: in ALIFE2, the absolute live birth difference was 0.7%, and with progesterone in bleeding it was 15% [24, 27]. Per-transfer results systematically favour PGT-A because they exclude women without a euploid embryo; per-patient or intention-to-treat results show no benefit [3, 81]. Negative trials (ALIFE, ALIFE2, Cochrane review of 9 trials) underpin the recommendation against anticoagulants, and the only favourable evidence for PGT-SR and PGT-A comes from observational or retrospective studies [1, 3, 27]. Registrations of ongoing trials are in section 11.

7.9. Developments in the past twelve months

Between October 2025 and October 2026, the most relevant changes concerned documents and observational evidence, rather than regulatory authorisation.

Guidelines. On 29 April 2026, ASRM published the committee opinion replacing its 2012 document, with the definition of two or more losses, recommendation to offer genetic POC analysis to all patients from the second miscarriage, parental karyotyping only for unbalanced or unanalysed POC, and a restrictive position on PGT-A [3]. On 30 October 2025, SOGC published guideline No. 464, with POC analysis after two first-trimester losses and a conditional recommendation for PGT in translocation carriers, differing from ESHRE and RCOG [4]. A commentary published in June 2026 criticises SOGC for underusing CMA and NGS and advocates conditional use of PGT-A and PGT-SR in selected patients (opinion) [65].

Observational studies and reviews. Publications included CMA and exome studies in POC from Urumqi, India and Vietnam (observational human studies) [42, 70, 71], the Italian cfDNA study after miscarriage [68], the Human Intolerome database (curated tool, published in March 2026) [41], the review of maternal variants associated with aneuploid conceptions proposing “predisposition to aneuploidy” as a diagnostic dimension (narrative review) [54], the review of NLRP7 in mole and GTN proposing genotype-stratified oncological surveillance (narrative review, published in July 2026) [49], and a review regarding PGT-A as beneficial in older patients (narrative review) [75]. Genome sequencing in 118 families with unexplained euploid RPL was released as a preprint in October 2025, without peer review [72]. The 17-year prospective Indian cohort on GTN in biallelic recurrent mole was published in 2025 [26].

Regulatory. In the sources consulted, there was no authorisation, opinion or label change concerning drugs for RPL during this period. The ESHRE website lists no guideline update later than the January 2023 version [1].

7.10. Pregnancy, lactation, perioperative setting and transition

In women with hereditary thrombophilia requiring anticoagulation during pregnancy for VTE risk, warfarin is teratogenic and should be replaced with heparin [12]. Surgical evacuation of miscarriage facilitates tissue acquisition for genetic analysis, but home collection after medical management is also possible [3]. In female translocation carriers, invasive prenatal diagnosis has low attributable miscarriage risks (section 8.7). IVF reproductive interventions carry their own risks: mild ovarian hyperstimulation syndrome in 8–23% and severe in 0.1–2% of cycles [78]. Counselling adolescents known to carry rearrangements, or sisters of women with biallelic maternal-effect gene variants, forms part of transition to adulthood and is discussed in section 8.8.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

Counselling a couple with RPL depends on the identified cause. Table 8.1 gathers risks described in the sources; values are estimates from series with ascertainment bias and should be presented as orders of magnitude.

Table 8.1. Recurrence and affected offspring risks by genetic scenario

8.2. Reciprocal translocations: risk estimation

Precise calculation of viable imbalance risk is neither feasible nor necessary; the Oxford Desk Reference uses risk bands (below 0.5%, 0.5–1%, 1–5%, 5–10% and above 10%) and four complementary approaches: family history, calculation of the imbalance's HAL, empirical Stene and Stengel-Rutowski data, and literature and database searches such as DECIPHER [13]. The algorithm has six steps: define breakpoints and draw the pachytene diagram; make a rough estimate from family history and segment lengths (unbalanced live birth risk exceeds 10% when there is a family history of affected term pregnancies or the proband was a malformed fetus); assess whether the product with the smallest imbalance is viable; assess 3:1 segregation, more likely with acrocentrics; refine through HAL, empirical tables and literature; and classify within a risk band [44]. Computational approaches ignore differences in gene density, and empirical approaches suffer from ascertainment bias [13]. Prediction requires knowledge of the chromosomes involved, segment type and size, and carrier sex [3, 45]. An annotated photograph and ideogram of the chromosomes involved help explain the rearrangement to the couple [44]. There is no indication that parents with a structural abnormality have an increased risk of a child with a chromosomal abnormality independent of the rearrangement [44].

Options are further natural conception, with prenatal diagnosis by CVS or amniocentesis, PGT-SR and donor gametes (section 7.2) [2, 3]. In prenatal diagnosis, karyotyping is the cornerstone, and genomic array is much more sensitive for subtle imbalances but does not distinguish balanced carriers from normal karyotypes [44]. In couples with an adverse obstetric history and segregation apparently biased towards unbalanced products, IVF with preimplantation testing may be an option [44].

8.3. Robertsonian translocations

Table 8.2. Risk of a child with aneuploidy or UPD when one parent has a heterologous Robertsonian translocation [14]

The 0.65% UPD risk observed in fetuses with a balanced Robertsonian translocation translates into an overall risk below 0.5%, because some fetuses have a normal karyotype [14]. In rob(13q14q), none of 222 carrier pregnancies resulted in a live birth with translocation trisomy 13, although translocation trisomy 13 was found in 13 of 42 amniocenteses and there were 5 stillbirths after 28 weeks; the 20-week ultrasound has an approximately 90% probability of detecting signs of trisomy 13, and, given the low risk and frequent history of miscarriage or subfertility, amniocentesis may be preferable to CVS [14]. In maternally transmitted rob(14q21q), with a 10–15% Down syndrome risk, invasive prenatal diagnosis should be discussed; in paternal transmission the risk is lower, but it is also offered [14]. Families with recurrent miscarriage or subfertility may prefer screening (nuchal translucency, anomaly ultrasound, biochemical screening), knowing they retain a significant residual risk even with normal screening [14]. When a Robertsonian translocation involving chromosome 14 or 15 is detected prenatally, fetal UPD risk is 0.65%, ultrasound does not assess it accurately, and specific testing uses amniocyte DNA with parental blood [14].

In familial homologous Robertsonian translocations, such as rob(13q13q) or rob(21q21q), the reproductive outlook with own gametes is very adverse, and options are donor gametes (donor sperm insemination or donor oocytes) or adoption [14]. In a de novo Robertsonian translocation detected prenatally, phenotypic risk is very low, limited to UPD14 or UPD15 (approximately 0.65%), and recurrence with normal parental karyotypes is low, certainly below 2% [14]. In managing a couple with a Robertsonian translocation and recurrent miscarriage without another cause, reassurance should be given that most couples eventually have a normal pregnancy [14].

8.4. Inversions

In inversion carriers, risk depends on size, type and chromosomes involved; it is higher in large symmetrical pericentric inversions with breakpoints near the telomeres and those that may produce recombinants of chromosomes 13, 18 and 21, for which prenatal diagnosis is offered [47]. Without guidance from family history, risk should be discussed with the laboratory [47]. Incidentally discovered paracentric inversions carry low risk, and polymorphic pericentric variants require no specific counselling [47].

8.5. Aneuploidy, triploidy and mosaicism

An aneuploid miscarriage does not indicate an increased aneuploidy risk in the next pregnancy beyond age-related risk, and parental chromosomal analysis is not indicated in triploidy [6, 33]. Recurrent digynic triploidy has been reported in only a few families, and prenatal diagnosis in future pregnancies is discretionary [6]. After a partial mole, the woman should be registered for hCG monitoring because of an approximately 0.5% malignant transformation risk [6]. In confined placental mosaicism, recurrence is negligible when due to mitotic nondisjunction and low when due to trisomy rescue (through possible germline mosaicism); prenatal diagnosis in a future pregnancy may be offered for reassurance [48].

8.6. Maternal-effect genes

In a woman with biallelic variants in a maternal-effect gene, parents are presumed heterozygous; each sister has a 25% probability of being biallelic (with reproductive complication risk), 50% of being heterozygous (presumed low risk, still under study) and 25% of not being a carrier, and male siblings have no related reproductive risk [7]. NLRP7 variants in men do not alter spermatogenesis, and NLRP7 heterozygosity may increase early miscarriage according to the review by Cozette and colleagues [43]. Exact risks of each reproductive outcome are unknown because data are scarce [7]. There is no reliable prenatal test for multilocus methylation changes, prenatal sequencing of the maternal variant is not justified (offspring are heterozygous), and preimplantation diagnosis is not possible; mole may be identified by ultrasound [7]. DNA banking should be considered [7]. In biallelic recurrent mole, oocyte donation is the reproductive option with documented results (section 7.4) [8, 49].

8.7. Prenatal diagnosis

Prenatal diagnosis in rearrangement carriers uses CVS or amniocentesis, with karyotyping and array; CVS produces more uncertain results through mosaicism, relevant to CPM [44, 90]. In the meta-analysis by Akolekar and colleagues, miscarriage before 24 weeks occurred in 0.81% (95% CI 0.58–1.08) after amniocentesis versus 0.67% in controls, with a weighted attributable risk of 0.11% (95% CI −0.04 to 0.26), and in 2.18% (95% CI 1.61–2.82) after CVS versus 1.79% in controls, with an attributable risk of 0.22% (95% CI −0.71 to 1.16) [90].

8.8. Cascade testing and counselling minors

Chromosomal analysis should be offered to adult relatives at risk of carrying a rearrangement; when a rearrangement is identified prenatally or in a child, the recommendation for genetic counselling during adolescence should be recorded [14]. Before testing relatives or performing prenatal diagnosis, the known carrier should have a report defining the breakpoints; at-risk individuals are karyotyped when their status is unknown and they are old enough to consent [44]. Cascade screening is generally not performed when viable imbalance risk is below 0.5%, because it may generate unnecessary anxiety [47]. In families with biallelic maternal-effect gene variants, testing adult sisters identifies those with reproductive risk [7]. Consistent with that recommendation, carrier testing in minors without medical benefit during childhood should be deferred until they can participate in the decision [14].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

RPL frequency depends on its definition. With a threshold of two or more losses, ESHRE estimates that RPL affects approximately 1–2% of couples [24]. The population meta-analysis in the “Miscarriage matters” series estimated the proportion of women with one miscarriage at 10.8% (95% CI 10.3–11.4), two miscarriages at 1.9% (1.8–2.1) and three or more at 0.7% (0.5–0.8); with a three-miscarriage threshold, RCOG estimates approximately 1% of women, and second-trimester miscarriage affects another 1% [2, 23]. These figures measure prevalence among women who have become pregnant, not incidence per pregnancy. Approximately 23 million miscarriages occur worldwide annually, approximately 44 per minute [23]. The estimate of approximately 5% of women presented in a preprint abstract is not supported by guidelines [72].

Genetic cause frequency also depends on the referred population: parental rearrangement frequency was 4.7% in Québec (more than 22,000 couples with two or more miscarriages, 1990), 1.9% in the United Kingdom (20,432 parents), 3.5% in a series of 795 couples and 11.7% with low-coverage sequencing in China (1077 couples) [1, 2, 5, 37]. Balanced reciprocal translocations occur in more than 0.1% of the general population and Robertsonian translocations in approximately 1/1000 [13, 14].

9.2. Regional data and founder populations

USA. ASRM relies on North American data for age-related aneuploidy (approximately 50% below 35 years and 75% above 40) and the SART-CORS registry for PGT-A [3]. The Pittsburgh reciprocal translocation carrier series and genome sequencing in 118 families from Stanford, UCSF and Pittsburgh are the main North American genomic series [45, 72]. Trio exome sequencing in fetuses with structural anomalies in New York had a 10% yield [39].

Europe. In the United Kingdom, the four-centre audit (20,432 parents) and PAGE study (610 fetuses, England and Scotland) are the reference series [2, 40]. In the Netherlands, the six-genetics-centre study (1992–2000) compared 278 carrier and 427 non-carrier couples [62]. In Denmark, the national registry underpins the Kolte and Westergaard prognostic tool adopted by ESHRE, still without external validation, and counted 183 triploid pregnancies in 1.5 million pregnancies [6, 24]. Prognostic class II HLA typing is permitted only in Scandinavian women with secondary RPL after a son [1]. ALIFE2 recruited mainly in the United Kingdom and Netherlands [27]. In Europe, FVL heterozygosity ranges from 2–3% in Italy and Spain to 10–15% in southern Sweden and Greece, and prothrombin variant heterozygosity is approximately 3% in the south and 1.7% in the north [17].

USA by ancestry. FVL heterozygosity is 5.2% in Americans of European origin, 2.2% in Hispanic Americans, 1.2% in African Americans, 1.25% in Native Americans and 0.45% in Asian Americans; prothrombin variant heterozygosity is 2–5% in people of European origin, 2.2% in Hispanic people and 0–0.6% in African Americans [17]. Sporadic miscarriage is more frequent in Black African or Caribbean women than White European women according to RCOG [2].

Asia and the Middle East. Low-coverage sequencing of couples (China), CMA of 1585 miscarriages (Urumqi), PGT-SR in 194 couples (China), POC studies in India and Vietnam, and Japanese registry data cited by ESHRE are the main Asian series [1, 37, 42, 63, 70, 71]. In Saudi Arabia, molecular autopsy in consanguineous families had a 63.8% yield, and variants of the maternal-effect gene TLE6 were described in Saudi families [11, 73]. Families with biallelic recurrent mole frequently have consanguinity and familial clustering, and published series include Pakistani, Tunisian, Indian and Iranian patients [9, 15, 26, 43]. Complete mole occurs in approximately 1/1000 and partial mole in 3/1000 pregnancies in Western countries, and both in approximately 8/1000 in Southeast Asia, according to the review by Cozette and colleagues [43]. There is no population estimate for biallelic recurrent mole; Orphanet gives prevalence as “unknown” [8, 18].

Portugal and Brazil. The sources consulted include no data from Portugal or Brazil on the frequency of RPL, parental rearrangements or maternal-effect gene variants; absence from the sources consulted does not mean absence of published data.

9.3. Special populations

Women aged 40 or older have twice the probability of miscarriage of those aged 20, partly because of a higher frequency of chromosomally abnormal conceptions [5], and their ovarian reserve limits the number of embryos available for PGT [1, 3]. ESHRE notes more blastocyst aneuploidy and more cycles without transfer in women with unexplained RPL and diminished ovarian reserve [1]. Consanguineous couples have a greater probability of fetal recessive monogenic causes and of biallelic recurrent mole [9, 73], although RCOG found no demonstrated association between consanguinity and recurrent miscarriage overall [2]. Male Robertsonian translocation carriers may present with infertility and oligospermia [14].

9.4. Referral networks and patient organisations

There is no ERN dedicated to RPL in the sources consulted. ERN ITHACA (rare malformation syndromes and intellectual disability) is relevant to offspring with chromosomal imbalances or syndromes [28]. EOTTD is the European network for gestational trophoblastic disease; the sources consulted do not confirm that ERN EURACAN formally includes trophoblastic disease [29]. In the United Kingdom, hCG follow-up after mole is provided by registration centres (www.hmole-chorio.org.uk) [6]. ESHRE publishes a patient leaflet based on the 2022 guideline [91]. Among patient organisations, Unique supports chromosomal rearrangement carriers and their families [92]; the Oxford Desk Reference also lists the Miscarriage Association (United Kingdom), ARC (Antenatal Results and Choices), SOFT UK and the Down's Syndrome Association [5, 14, 48]. The Miscarriage Association participated in the ESHRE guideline development group [91].

10. Illustrative Clinical Case

In 2020, Cozette and colleagues described a French woman aged 30 years, with six pregnancies and one delivery, whose first pregnancy ended in spontaneous miscarriage and the next three in complete hydatidiform mole, confirmed by a reference-centre pathologist, with negative p57 immunohistochemistry in villous mesenchyme and trophoblast [43]. Molecular genotyping of the moles was unavailable, so their androgenetic or biparental origin was unknown, and there was no family history of losses [43]. Sanger sequencing of all NLRP7 exons and intronic boundaries identified two variants, classified by the authors as of uncertain significance: c.2982-2A>G, with a predicted splicing effect, and a 14-base-pair duplication in exon 4 with a frameshift and premature termination codon, described as Y318CfsX7 [43]. Figure 1 of the article shows the electropherograms: on the left, the heterozygous A-to-G change; on the right, the 14-nucleotide duplication with overlapping peaks from the frameshift point (https://pmc.ncbi.nlm.nih.gov/articles/PMC7492304/figure/Fig1/) [43]. The patient's parents were unavailable and variant phase was not determined; her partner's semen analysis was normal [43].

The patient entered an oocyte donation programme: four mature oocytes were obtained, fertilised by ICSI, and two embryos transferred on day 3 [43]. The pregnancy was singleton and uncomplicated; after failed induction at 41 weeks and 2 days, she underwent caesarean delivery of a girl weighing 2895 g [43]. She developed postpartum pre-eclampsia treated with an oral antihypertensive, which resolved; the placenta was normal and hCG decline was normal [43]. Months later, spontaneous pregnancy resulted in another complete mole, confirmed histologically, and the couple awaited further oocyte donation [43].

The case illustrates four points. First, oocyte donation allows a normal pregnancy in a woman with recurrent mole because the defect lies in the oocyte [8, 43]. Second, spontaneous conception after a donor-oocyte birth retains the mole risk [43]. Third, without determined phase or molar tissue genotyping, it cannot be stated that the two variants are biallelic or that the moles were biparental; current consensus recommends tissue genotyping and variant classification according to ACMG/AMP criteria [25, 36]. On MANE transcript NM_001127255.2, c.2982-2A>G is valid (NC_000019.10:g.54923874T>C), but it cannot be confirmed as corresponding to the transcript used by the authors, and the second variant has no published c. designation [43, 58]. Fourth, the authors state that recurrent forms of complete mole carry no malignant degeneration risk; this assertion is contradicted by the prospective Indian cohort, in which 50% of women with biallelic NLRP7 developed GTN, and by the 2026 review, and hCG surveillance after each pregnancy remains indicated [26, 43, 49].

11. Prognosis and Long-Term Follow-up

11.1. Reproductive prognosis

RPL prognosis is favourable in most cases: 50–80% of women succeed in the next attempt without specific intervention [3]. ESHRE recommends (strong) basing prognosis on the woman's age and complete history (number of losses, live births and their sequence), and replaced earlier tools with the Kolte and Westergaard tool, derived from the Danish national registry and still without external validation [24]. The risk of another miscarriage rises with the number of previous miscarriages, from 11.3% without previous miscarriage to 63.9% after six [2]. POC analysis results modify prognosis: after an aneuploid miscarriage, the probability of subsequent live birth was 68%, versus 41% after a euploid miscarriage in one series; the more euploid miscarriages, the higher the probability of another miscarriage [2, 5]. This relationship does not apply to parental abnormalities [2].

In balanced rearrangement carriers, miscarriage risk is higher, but the probability of a healthy child is similar to non-carriers (83% versus 84% in the Dutch study) and cumulative live birth rates are good without PGT (64% in one series; up to 70–71% in others) [1, 3, 62]. In reciprocal translocation carriers, the risk of an unbalanced pregnancy surviving into the second trimester is 0.8%, and of a child with disability due to imbalance 0.02%, in the database cited by RCOG [2]. In recurrent mole with biallelic NLRP7, prognosis with own oocytes is very adverse (1 spontaneous live birth in 22 biallelic women in the Indian cohort) and GTN risk is high (50% of women with biallelic NLRP7 in the same cohort), with trophoblastic disease cure in more than 98% of cases treated in the United Kingdom [6, 26]. With donated oocytes, 3 of 4 women had live births [26]. In the long term, RPL is associated with greater cardiovascular disease, stroke, diabetes, autoimmune disease, VTE and mental illness risks, and obstetric complications in future pregnancies [3, 23].

11.2. Surveillance and follow-up

Table 11.1. Surveillance and follow-up in genetically caused RPL

The sources consulted do not specify intervals for hCG measurement or cardiovascular assessment; hCG intervals follow trophoblastic disease centre protocols.

11.3. Ongoing trials and studies

The Yale University observational study of genomic predictors of RPL (500 participants, starting September 2021, expected primary completion December 2026) was recruiting at its last update in May 2026, without results [93]. A randomised trial of non-invasive PGT-A versus morphological selection in women with RPL undergoing IVF (Hong Kong, 152 participants, primary outcome miscarriage rate) has had unknown status since 2023 [80]. Two Shanghai trials of preimplantation genetic screening in RPL, one with 710 participants and live birth per initiated cycle as the outcome and the other with 189 infertile women, completed in 2016, have no registry results [79, 94]. None of these trials compares IVF with PGT-A against expectant management.

12. Summary and Final Considerations

Recurrent pregnancy loss is now defined by ESHRE, ASRM and SOGC as loss of two or more pregnancies, whereas RCOG retains three miscarriages and the 2017 Oxford Desk Reference still uses three consecutive losses. It affects approximately 1–2% of couples and mostly has a good prognosis without intervention. The most frequent genetic cause is sporadic aneuploidy of the conceptus, dependent on maternal age, accounting for approximately half of sporadic miscarriages and approximately 40% of miscarriages in women with RPL, with its proportion decreasing as the number of losses increases. Parental balanced structural rearrangements are found in approximately 2% of referred parents, increase miscarriage risk without substantially reducing the probability of a healthy child and entail an unbalanced live birth risk dependent on rearrangement type, chromosomes, segments and carrier sex. Biparental diploid recurrent hydatidiform mole is an autosomal recessive maternal-effect disorder, caused mainly by biallelic NLRP7 variants and, less frequently, KHDC3L, MEI1, TOP6BL and PADI6, in which the healthy woman cannot achieve a normal pregnancy with her own oocytes and has a high trophoblastic neoplasia risk; oocyte donation is the reproductive option with documented results, and the cohort finding of 50% GTN contradicts earlier assertions of no malignant risk. Fetal monogenic causes, including male-lethal X-linked dominant disorders and autosomal recessive lethality, account for some euploid losses, with exome and genome yields varying greatly between populations.

Assessment starts with chromosomal POC analysis using array-based techniques or sequencing, recommended by ASRM from the second miscarriage, SOGC after two first-trimester losses, RCOG from the third and ESHRE only for explanatory purposes. Parental karyotyping is reserved by ESHRE, RCOG and ASRM for individual risk assessment, POC with structural imbalance or absent POC analysis. Hereditary thrombophilias have a weak association with first-trimester loss, should not be routinely screened for and should not be treated with heparin to prevent loss, as confirmed by ALIFE2; antiphospholipid syndrome is the differential diagnosis with effective treatment. PGT-SR may reduce miscarriages in translocation carriers but has not been shown to increase live births or shorten time to pregnancy, and societies differ in their recommendations. PGT-A has not been compared with expectant management in any published randomised trial in RPL, and its utility is limited to shared decision-making in older women with proven aneuploid miscarriage.

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