Anembryonic Pregnancy and Sporadic Pregnancy Loss of Chromosomal Cause

Anembryonic pregnancy (gestational sac without an embryo) and sporadic early pregnancy loss due to aneuploidy, polyploidy or structural imbalance; cytogenetics and genomics of the products of conception; clinical management of first-trimester loss. Recurrent pregnancy loss, triploidy and mosaic trisomy 16 enter the differential diagnosis.

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview

Anembryonic pregnancy is a concept born of ultrasound. Before ultrasound imaging, first-trimester loss was recognised by bleeding and the passage of tissue, and the pathological examination of the products of conception sometimes described a chorionic sac without an embryo. In 1972, Donald, Morley and Barnett published in the Journal of Obstetrics and Gynaecology of the British Commonwealth the first work devoted to the sonar diagnosis of the blighted ovum, which established the term in the obstetric literature [45]. With transvaginal ultrasound, widespread from the early 1990s, it became possible to see the empty gestational sac weeks before any symptom, and the first diagnostic criteria (mean sac diameter of 16 mm without an embryo, or crown-rump length of 5 mm without cardiac activity) derived from these early studies [4].

Cytogenetic investigation of pregnancy loss preceded ultrasound. The large karyotype series of spontaneous miscarriages from the 1970s and 1980s established that about half of losses have a chromosomal anomaly: Boué, Boué and Lazar studied 1500 karyotyped miscarriages in France between 1966 and 1972 and estimated that one in two conceptions has a chromosomal anomaly, with a maternal age effect restricted to autosomal trisomies [46]; Hassold and colleagues karyotyped 1000 spontaneous miscarriages and found 46.3% anomalies, with no difference between five population groups and with maternal age as the only unequivocally associated factor, in trisomies [47]. In 1988, Wilcox and colleagues showed, with daily urinary hCG measurements in 221 women trying to conceive, that 22% of pregnancies are lost before being clinically detected and that total loss after implantation reaches 31% [34].

In 1991, Henderson and colleagues applied locus-specific minisatellite probes to the trophoblast of 14 anembryonic pregnancies and showed that this tissue always has maternal and paternal genomic contributions; the absence of an embryo, shared with the complete hydatidiform mole, does not therefore result from an androgenetic conceptus [48]. In the same year, Witter and colleagues described four cases in which an earlier scan had shown embryonic cardiac activity and the following scan showed a sac without a visible embryo, documenting that the ultrasound appearance of an empty sac may arise after the regression of an initially present embryo [49].

Systematic comparison between anembryonic pregnancies and missed abortions with an embryo began with karyotype series: Minelli and colleagues, in Italy, found 67% anomalies in 52 anembryonic pregnancies, with a predominance of trisomies 16 and 22 and absence of 45,X [36]; Lathi and colleagues, at a Stanford infertility clinic, found 58% anomalies in anembryonic and 68% in embryonic pregnancies, a non-significant difference [50]. The Tomsk series published by Nikitina and colleagues in 2023, with 1551 karyotyped miscarriages over 32 years, is the largest comparative karyotype series and includes a compilation of 12 studies [5]. The move from karyotyping to chromosomal microarray, from the mid-2000s, and exome and genome sequencing, in the following decade, expanded the diagnostic yield in products of conception and raised the question of unexplained euploid losses [35, 51, 52].

1.2. Nomenclature and reclassifications

Pregnancy loss terminology is inconsistent. The ESHRE Special Interest Group on Early Pregnancy published a consensus in 2015 recommending that classification be based on clinical findings and, whenever possible, on transvaginal ultrasound [2]. ACOG uses miscarriage, spontaneous abortion and early pregnancy loss as synonyms in the first trimester and adopts the last term [4]. The Oxford Desk Reference of clinical genetics describes miscarriage as a lay term for early spontaneous loss, defines early pregnancy loss as spontaneous miscarriage before 12 weeks, spontaneous miscarriage as loss before 24 weeks, missed abortion as fetal parts in the sac without cardiac activity before 24 weeks, and intrauterine fetal death as death after 24 weeks and before labour [3].

In 2024, the SRU consensus conference, with the participation of ACOG and other specialties, published a lexicon for first-trimester ultrasound. The term early pregnancy loss replaces pregnancy failure and is combined with modifiers («concerning for», «diagnostic of», «in progress», «incomplete», «complete»); «concerning for early pregnancy loss» replaces «suspicious for pregnancy failure». The lexicon advises against the terms blighted ovum, nonviable pregnancy, fetal pole, pseudosac, heartbeat and «alive/viable» in the first trimester. The term anembryonic pregnancy is reserved for a gestational sac of 25 mm or more without an embryo, or for the absence of an embryo on serial scans performed at discriminatory intervals; «embryonic demise» designates an embryo with a crown-rump length (CRL) of 7 mm or more without cardiac activity, and «fetal demise» applies from 11 weeks and 0 days. A survey included in the work showed that patients associate the word failure with blame and prefer miscarriage [1]. In Portuguese, «gestação anembrionada» corresponds to the recommended term; «ovo cego» and «ovo anembrionado» are colloquial equivalents of blighted ovum.

The World Health Organization (WHO) includes the empty sac in the definition of missed abortion: the pregnancy stops developing, the embryo, embryonic tissue or empty gestational sac remain in the uterus and the cervix is closed [43]. The definition of recurrent pregnancy loss has changed: the Oxford Desk Reference adopts three or more consecutive miscarriages [3], whereas ESHRE allows the diagnosis from two losses, consecutive or not [39].

1.3. Operational definitions in this article

Anembryonic pregnancy designates an intrauterine gestational sac that contains no embryo according to the ultrasound criteria in section 5. For embryological and research purposes it is subdivided into empty sac (without a yolk sac) and sac with a yolk sac but without an embryo. In the interpretation of Nikitina and colleagues, the presence of a yolk sac without an embryo indicates that the disturbance arose after segregation of hypoblast and epiblast, which occurs 6 to 7 days after fertilisation: the hypoblast, which gives rise to the yolk sac endoderm, continues to develop, and the epiblast, which gives rise to the three germ layers of the embryo, arrests. A completely empty sac indicates a disturbance before this separation, during implantation [5].

Missed abortion with an embryo (MA) designates a sac with an embryo without cardiac activity. Sporadic early pregnancy loss of chromosomal cause designates a first-trimester loss, isolated or not part of a picture of recurrent loss with a parental cause, in which the product of conception has a numerical (aneuploidy, polyploidy) or unbalanced structural chromosomal anomaly. The products of conception (POC) are the gestational tissue expelled or evacuated, in particular the chorionic villi, on which genetic analysis is performed.

1.4. Scope and related entities

This article covers anembryonic pregnancy as an ultrasound and cytogenetic entity, sporadic early loss of chromosomal cause, genetic analysis of the products of conception and first-trimester clinical management. Evaluation of the couple with repeated losses, parental karyotyping, translocations and inversions, preimplantation genetic testing and recurrent hydatidiform mole due to maternal-effect genes, triploidy, partial mole and diploid-triploid mixoploidy, mosaic trisomy 16, confined placental mosaicism and maternal uniparental disomy of chromosome 16, and monosomy X in live births (Turner syndrome) appear here as related entities.

2. Molecular Genetics and Pathophysiology

2.1. Meiosis, non-disjunction and the origin of aneuploidies

Most anomalies found in products of conception are de novo aneuploidies originating in meiosis. In the female, meiosis begins in the fifth month of fetal life, after about 33 mitotic cycles since fertilisation; the ovaries then contain about 8 million oocytes, reduced to 1 to 2 million at birth by apoptosis. By the sixth month of fetal life, oocytes pass from pachytene to diplotene and all remain arrested in prophase I until puberty and beyond; in each cycle, a cohort of oocytes resumes meiosis, completes the first division and arrests again at metaphase II until fertilisation. This prophase I, which may last more than four decades, is the biological basis of the maternal age effect [53]. In the male, spermatogonia divide by mitosis throughout adult life (about 265 cycles at 25 years, nine times more than in the female germline), which explains the higher rate of point mutation of paternal origin; male meiosis only begins at puberty [53].

Non-disjunction is the failure of separation of homologous chromosomes in meiosis I, or of sister chromatids in meiosis II and mitosis, and generates gametes or cells with an abnormal number of chromosomes. When it occurs after fertilisation (post-zygotic mitotic non-disjunction), it produces mosaicism [53]. Hassold and Hunt estimate that aneuploidy is present in at least 5% of clinically recognised pregnancies, that it is the leading genetic cause of pregnancy loss and that most aneuploid conceptuses die in utero [54].

Non-disjunction in maternal meiosis I is the main age-dependent mechanism. The risk rises exponentially with maternal age for trisomies 21, 18 and 13 and for the 47,XXX and 47,XXY karyotypes; in autosomal trisomies, the curve appears to plateau at the most advanced ages. The 45,X and 47,XYY karyotypes, triploidy and de novo structural rearrangements do not depend on maternal age [8]. In cleavage-stage in vitro fertilisation (IVF) embryos, Márquez and colleagues found aneuploidy in 3.1% of embryos from patients aged 20 to 34 years and in 17% of those from patients aged 40 years or over [8]. Robinson and colleagues studied 54 couples with two or more documented aneuploid or polyploid miscarriages and concluded that trisomies resulted predominantly from meiotic errors related to maternal age, even when the second miscarriage had the same anomaly; germline mosaicism, factors of chromosome structure or segregation, increased sperm aneuploidy or accelerated ovarian ageing did not appear to play a significant role, which does not exclude individual variation in risk [3].

Paternal age is associated with a lower pregnancy rate and a higher miscarriage rate, in natural conception and after intrauterine insemination, but there is little evidence of an increase in chromosomal anomalies: Wyrobek and colleagues found no association with trisomies 21, 18 and 13, Klinefelter and Turner syndromes, triple X or triploidy [55].

2.2. Spectrum of anomalies in products of conception

The classical distribution of anomalies in spontaneous miscarriages, compiled in the Oxford Desk Reference, is as follows [3]:

Modern series confirm this profile and show how the technique and sample selection alter the observed frequency:

Stephenson, Awartani and Robinson successfully karyotyped 420 products of conception from 285 couples with recurrent loss (29 preclinical, 237 embryonic and 154 fetal): 225 (54%) were euploid and 195 (46%) abnormal, of which 131 (66.5%) trisomic, 37 (19%) polyploid, 18 (9%) with monosomy X, 8 (4%) with an unbalanced translocation and one with combined trisomy 21 and monosomy X. The frequency of euploid miscarriages was higher in women under 36 years than in controls, but the distribution of anomalies did not differ from controls after stratification by maternal age [61]. The Oxford Desk Reference cites this study with the wrong denominator (225 instead of 420 products of conception) [3].

2.3. Anembryonic pregnancy versus missed abortion with an embryo

The central question of this article is whether the absence of an embryo is associated with a chromosomal cause different from that of miscarriage with an embryo. The Tomsk series answers it with the largest number of karyotyped cases [5]:

The overall frequency of anomalies was 57.1% (152/266) in AP and 52.9% (680/1285) in MA (p = 0.209). The 45,X karyotype occurred in 0.8% (2/266) of APs and in 5.0% (64/1285) of MAs (p < 0.001). As some mosaic tetraploidies may correspond to culture artefacts, the authors re-examined tetraploid samples by fluorescence in situ hybridisation (FISH) on uncultured tissue: confirmed tetraploidy was 5.3% (14/266) in AP and 1.7% (22/1285) in MA (p < 0.001). Maternal (28.3 versus 28.5 years) and paternal age, the number of previous pregnancies and miscarriages and the proportion of couples with recurrent loss (35.5% versus 39.4%) did not differ between groups; gestational age was lower in AP, both by last menstrual period (9.0 versus 9.5 weeks) and by ultrasound (6.6 versus 7.5 weeks) [5].

The same work compiles the published comparative studies, and the compilation shows a divergence between series [5]:

Overall, anembryonic pregnancies have fewer detected chromosomal anomalies than miscarriages with an embryo, but individual studies diverge. Other series point in the same direction as the pooled result: Gu and colleagues, with CMA in 1102 singleton losses in China, found an overall aneuploidy rate of 57.26%, higher in losses with a yolk sac or embryo than in losses without these structures (p < 0.001 and p = 0.001), and concluded that loss without a yolk sac or embryo may be less related to embryonic aneuploidy [62]; Zhu and colleagues, with multiplex ligation-dependent probe amplification (MLPA) in 1765 singleton IVF pregnancies, found 50.5% euploidy in AP versus 32.3% in losses with an embryo (p = 0.003) [63]. In the opposite direction, Minelli and colleagues found 67% anomalies in AP versus 53% in miscarriages with an embryo, with no significant difference [36], and Ozeren and colleagues, by flow cytometry on paraffin blocks, found abnormal ploidy in 40% (8/20) of APs versus 9% of spontaneous miscarriages in the same population (p < 0.05), with a lower S-phase fraction in AP [64]. In Colombia, in a series of 11 miscarriages before 12 weeks, four of the five abnormal karyotypes were APs, and mean β-hCG was 3.8 times higher in abnormal cases [65].

The series of Lathi and colleagues, which provides the 2007 row of the compilation, is retrospective and comes from a university infertility clinic (1999–2006): 272 missed abortions diagnosed by transvaginal ultrasound between 6 and 10 weeks and treated by office aspiration, with separation of villi from decidua before culture, mean maternal age 36.8 years and more than half of conceptions by IVF; AP was defined as absence of an embryonic pole at 7 weeks, and culture failed in 3 additional attempts. Among the 53 APs with an abnormal karyotype (of 91), there were 28 single autosomal trisomies, 8 multiple trisomies, 9 structural anomalies (deletions and additions), 5 tetraploidies, 2 monosomies X and 1 triploidy; among the 123 abnormal miscarriages with an embryo (of 181), there were 94 single trisomies, 9 multiple, 11 triploidies, 7 monosomies X, 2 tetraploidies and no structural anomaly. Trisomy 16 was the most frequent in both groups, and structural anomalies occurred only in APs. The 46,XX result occurred in 27% of APs and in 20% of miscarriages with an embryo, and the proportion of anomalies did not differ between miscarriages with and without documented cardiac activity (70% versus 59%; p > 0.05); the authors acknowledge that a 46,XX may reflect maternal contamination. The publication's table of characteristics gives 82 APs and 190 miscarriages with an embryo, whereas the results tables give 91 and 181, and the published percentages for triploidy and tetraploidy in APs do not match the counts; the values above are the absolute counts [50].

Three factors explain part of the discordance. The first is selection: series from infertility and IVF clinics have older women and selected embryos. The second is technique: karyotyping requires culture, which fails and favours the growth of maternal cells, and maternal contamination generates false 46,XX results; mosaic tetraploidy may be a culture artefact; CGH and MLPA do not detect balanced polyploidies. The third is definition: «empty sac» and «sac with a yolk sac without an embryo» have different frequencies of anomalies in the study by Li and colleagues (28.1% versus 43.4%) [5]. The sex ratio in miscarriages with a normal karyotype is an indirect indicator of maternal contamination: in the Tomsk series it was 0.54 in AP and 0.74 in MA (p = 0.142), and an earlier study from the same laboratory showed an inverse relationship with the severity of arrest (0.77 in miscarriages without developmental delay, 0.60 in MA, 0.31 in AP, versus 1.10 in elective terminations), which the authors relate in part to contamination by maternal cells [5].

Henderson and colleagues showed that AP trophoblast is biparental, which separates AP from the androgenetic complete mole; of the three karyotyped cases, two were 46,XX and one 47,XX,+16, with a sex ratio (6 male to 8 female) not differing from that expected [48]. Alberry and colleagues detected DNA of fetal origin (Y chromosome DYS14 sequence) in the plasma of pregnant women with male APs, at a median concentration equal to that of normal pregnancies (148.3 versus 145.8 genome equivalents per millilitre), which confirms that «fetal» cell-free DNA derives from the trophoblast and supports the use of maternal cfDNA in AP [66].

2.4. Specific anomalies and their timing of lethality

Autosomal trisomies. They are the most frequent group in all series and predominate in AP. Trisomy 16 accounts for 30% of trisomies in miscarriages [3], is the most frequent in the Thai AP series studied by BACs-on-Beads (15% of APs, followed by trisomies 22 at 9.6%, 15 at 3.8% and 19 at 3.8%) [37], and is the most common in cfDNA from spontaneous miscarriages in Italy [67]. Minelli and colleagues found trisomies in 74% of anomalies in APs versus 35% in miscarriages with an embryo, with a predominance of trisomies 16 and 22 [36]. Complete trisomy 16 is always lethal; mosaic forms and confined placental mosaicism allow survival. In Robertsonian translocations, trisomies 14 and 15 invariably fail, and most trisomies 22, many trisomies 13 and some trisomies 21 also end in miscarriage [68].

Trisomies compatible with birth. Even trisomies that can reach term are largely lost during pregnancy. Between about 11 weeks and term, 43% of pregnancies with trisomy 21 are lost, and between 16 weeks and term about 23% [69]. Trisomy 18 has a spontaneous loss rate of 36% from the second trimester onwards [70] and trisomy 13 of 64%; most conceptions with trisomy 13 end in spontaneous miscarriage, and about 90% result from non-disjunction in maternal meiosis I [71].

Tetraploidy. More frequent in AP than in MA, with confirmation by FISH on uncultured tissue; the authors interpret it as an anomaly that halts development earlier [5]. It accounts for 5% of anomalies and 2.5% of miscarriages in the classical compilation [3].

Triploidy. One of the most frequent aberrations in first-trimester miscarriages (about 7.5% of all miscarriages), unrelated to maternal age. The digynic form (two maternal sets) results from incorporation of the second polar body; the diandric form (two paternal sets) results from dispermy [72]. It is less frequent in AP than in MA (4.9% versus 8.9%), and the authors of the Tomsk series raise the hypothesis, as yet undemonstrated, that diandric triploidy favours the trophoblast through an imprinting effect and may give rise to the phenotype of a sac without an embryo [5].

Monosomy X. Up to 99% of 45,X conceptions are lost as spontaneous miscarriages, and intrauterine lethality between 12 and 40 weeks is about 65% [73]. In 80% of 45,X conceptions the paternal contribution is missing, which may result from post-zygotic loss [8]. Monosomy X is rare in AP and frequent in miscarriages with an embryo in almost all comparative studies; the interpretation is that monosomy X does not prevent early embryonic development and that these embryos die later, possibly through trophoblast failure [5]. In a cohort of 21,311 fetuses studied in Zhengzhou, monosomy X or 45,X mosaicism occurred in 7.03% of early miscarriages (before 12 weeks) versus 0.40% of the remaining losses, and mothers of 45,X conceptions were younger (29.88 versus 31.43 years) [74].

Structural imbalances. They account for 2% of miscarriages, half de novo and half inherited from a parent carrying a balanced rearrangement [3]. The viability of an imbalance follows an empirical rule: 95% of published viable autosomal imbalances lie within a triangle bounded by 4% trisomy and 2% monosomy of the haploid genome (about 120 and 60 Mb); outside it, the imbalance tends to end in spontaneous loss, although gene density and dosage sensitivity are not uniform [75]. In CMA series, clinically significant CNVs occur in 1.6% of products of conception with a normal karyotype [51]. A Russian study cited by Nikitina and colleagues found more CNVs in AP than in MA (299 versus 132), with deletions (54.3%) and duplications (45.7%) in AP and only duplications in MA [5].

Whole-genome uniparental disomy. Detectable only by SNP-array, it occurred in 0.4% of cytogenetically normal products of conception [51] and in two of 564 miscarriages [59].

2.5. Mosaicism

Mosaicism designates the presence, in the same conceptus, of two or more genetically different cell populations. Fetus, placenta and membranes derive from the same egg, but mitotic non-disjunction, trisomy rescue or a new somatic mutation break this identity. In post-zygotic non-disjunction of an autosome, the monosomic line is lost; for the X chromosome, it may persist (45,X/46,XX/47,XXX). Confined placental mosaicism is type 1 when limited to the cytotrophoblast, type 2 when limited to the chorionic stroma and type 3 when it affects both; pseudomosaicism is a line arising in culture [76]. In prenatal diagnostic chorionic villus sampling (CVS), confined placental mosaicism occurs in 1.9% and true fetal mosaicism in 0.19% [77]. These mechanisms explain why the tissue studied in a miscarriage, which is mostly trophoblast, may not represent the embryo.

2.6. Euploid losses: submicroscopic CNVs and monogenic causes

About 40% to 50% of products of conception are euploid by CMA, and the causes of these losses remain largely unexplained [52]. Exome sequencing (WES) in euploid products of conception has given yields between 3.5% and 26.5% in recent series: in a series of 66 euploid products of conception under 12 weeks, 13 cases (19.7%) with a high-confidence diagnosis (a 21q22.12-q22.3 duplication including DYRK1A and RUNX1 and pathogenic or likely pathogenic variants in CPLANE1, DHCR7, DSG2, DVL1, F5, NF1, RBM8A, SLC6A1 and VWF) and 9 (13.6%) with suggestive but inconclusive findings [78]; in India, 18 additional cases (10.46%) in 172 products of conception [79]; in Vietnam, 3.5% with clinical exome, mostly FGFR3 variants associated with skeletal dysplasia [80]; in Urumqi, 26.47% in 34 CMA-negative cases from women with recurrent loss, including variants in MOS (oocyte maturation) and TTC7A [60]. Yields depend on case selection (later losses, malformations, recurrent loss), gestational age and classification criteria, and are not comparable with each other. The Intolerome database brings together 934 genes essential for human viability, of which 59 (6.3%) are linked to first- and second-trimester miscarriages, and identifies 39 autosomal recessive genes with potentially lethal heterozygous variants at a frequency of 1/100 or more in all gnomAD v4.1.0 ancestries [81]. For anembryonic pregnancy itself, the sources consulted do not describe specific exome series.

2.7. Maternal predisposition to aneuploidy

Embryonic aneuploidy also has a hereditary maternal component, still under investigation. McCoy and colleagues associated common maternal variants on chromosome 4, in the PLK4 region, with aneuploidy of mitotic origin in day-3 IVF embryos, and showed that mothers with high-risk genotypes contributed fewer embryos on day 5 [7]; in a reanalysis of 24,653 blastomere and 17,051 trophectoderm biopsies, 4.7% of blastomeres had hypodiploid karyotypes characteristic of tripolar segregation, strongly associated with the PLK4 variants [82]. A 2026 review of 28 studies classifies candidate genes into meiotic recombination, spindle dynamics, checkpoint and maternal-to-zygotic transition, and assigns the strongest evidence to rare likely pathogenic variants in KIF18A, ELL3 and CEP120 and to common variants in PLK4 and CCDC66; HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7 and TLE6 appear on commercial infertility panels, but the direct association with aneuploidy requires validation [6]. These genes currently have no clinical utility in counselling after a sporadic loss.

2.8. Proposed non-chromosomal mechanisms for anembryonic pregnancy

Because the overall frequency of anomalies in AP does not differ from that in MA in the Tomsk series, the authors advocate searching for causes at other levels: microstructural rearrangements, monogenic variants, imprinting disturbances and other epigenetic modifications [5]. A 2026 translational study found dysregulation of amino acid metabolism in the serum of women with AP and, in villous RNA, 903 genes with differential alternative splicing and 558 differentially expressed genes; PRKCD, SCARB1 and METTL2B showed preferential exon inclusion, and SCARB1 was predicted as a target of the transcription factor TEAD4 [83]. This is a mechanistic hypothesis without clinical application.

2.9. Nomenclature

There are no sequence variants to standardise in Human Genome Variation Society (HGVS) notation; karyotypes are written according to the International System for Human Cytogenomic Nomenclature (ISCN). QF-PCR results describing copy number per chromosome are translated into ISCN equivalents only when the technique covers the genome; in the case in section 10, for example, the formula 48,XX,+16,+22 is an equivalence and not a karyotype, because the QF-PCR used studied only chromosomes 13, 15, 16, 18, 21, 22, X and Y [84]. The NLRP7 founder variants mentioned in section 9 (for example, R693W or L750V), among the maternal-effect genes of the differential diagnosis (NLRP7, KHDC3L, NLRP2, NLRP5, PADI6), are written in the abbreviated protein form used by OMIM (historical numbering), with the equivalent on the MANE transcript NM_001127255.2 given in section 9 [14].

3. Clinical Spectrum and Manifestations by System

3.1. Frequency of pregnancy loss and what each figure measures

Frequency estimates vary with the denominator. ACOG states that early loss affects 10% of clinically recognised pregnancies and that about 80% of losses occur in the first trimester [4]; Nikitina and colleagues cite 10% to 15% of clinically recognised pregnancies [5]. The Oxford Desk Reference reproduces the table of Jauniaux and colleagues (Emery and Rimoin, 4th edition, 2001), which includes losses before clinical diagnosis [3]:

The cohort of Wilcox and colleagues, with 707 cycles and daily urinary hCG measurement, showed that 22% of pregnancies are lost before clinical recognition and that total loss after implantation is 31%; 95% of women with subclinical loss achieved a clinical pregnancy within two years [34]. In national registries, which mainly count losses with hospital contact and underestimate very early losses managed as outpatients, 13.5% of intended pregnancies ended in fetal loss in Denmark between 1978 and 1992 (634,272 women, 1,221,546 outcomes) [85]. The loss rate decreases with gestational age, and gestational age, maternal age and previous history are its most important determinants [3].

3.2. Maternal age and reproductive history

The risk of miscarriage rises with maternal age in all series. ACOG gives 9% to 17% at 20–30 years, 20% at 35, 40% at 40 and 80% at 45 years, from secondary data [4]. In the Danish registry, the risk was 8.9% at 20–24 years and 74.7% at 45 years or over, and at 42 years more than half of pregnancies ended in loss; the age effect was independent of previous miscarriages, parity and period [85]. In the Norwegian registry of 421,201 pregnancies (2009–2013), the lowest risk was 10% at 25–29 years, rose after 30 and reached 53% at 45 years or over [86]. A 40-year-old woman is twice as likely to miscarry as a 20-year-old, partly because of the greater risk of a chromosomally abnormal conception [3]. Advanced maternal age increases the loss of both aneuploid and euploid conceptions [8].

The difference between the Norwegian (53%) and Danish (74.7%) estimates at 45 years or over reflects different periods, registry sources and handling of outcomes, and neither measures preclinical loss.

3.3. Natural history of anembryonic pregnancy

Anembryonic pregnancy is lost earlier than miscarriage with an embryo: in the Tomsk series, the mean ultrasound gestational age was 6.6 weeks in AP and 7.5 in MA, with equal maternal ages [5]. The clinical presentation does not distinguish the types of loss. Vaginal bleeding and uterine cramps also occur in normal pregnancy, ectopic pregnancy and molar pregnancy, and confirmation depends on ultrasound [4]. The sac of a non-viable pregnancy continues to grow, more slowly: in a London cohort of 1060 pregnancies of uncertain viability, the MSD grew on average 1.003 mm per day in viable pregnancies and 0.503 mm per day in non-viable ones, with no growth threshold that safely excludes viability [87]. The empty sac may correspond to an initial failure, before or shortly after implantation, or to an embryo that regressed after having had cardiac activity [5, 49].

Without intervention, complete expulsion eventually occurs in most women: given sufficient time (up to 8 weeks), expectant management achieves complete expulsion in about 80%, and is more effective in symptomatic women or those with incomplete expulsion than in those with missed abortion or anembryonic pregnancy [4]. In the North American trial of medical treatment with misoprostol, success was lower in anembryonic pregnancy (81%) than in embryonic or fetal demise (88%) and in incomplete or inevitable loss (93%), but a later multivariable analysis showed that only active bleeding and nulliparity predicted success [4].

3.4. Complications

Serious complications are rare and comparable between approaches: haemorrhage requiring admission or transfusion occurs in 0.5% to 1% and pelvic infection in 1% to 2% [4]. In the British MIST trial (Miscarriage Treatment), with 1200 women under 13 weeks, confirmed infection within 14 days was 3% with expectant management, 2% with medical and 3% with surgical management [88]. A prolonged course without expulsion, heavy bleeding or fever change management (section 4). Persistent gestational trophoblastic disease is a complication of moles, not of AP; when ultrasound suspicion of a mole is not confirmed by histology and genotyping, post-molar follow-up does not apply (section 10) [84].

3.5. Psychological impact

Early loss has emotional consequences that guidelines recognise as part of care: the National Institute for Health and Care Excellence (NICE) recommends treating women with dignity, training professionals and non-clinical staff, offering a follow-up appointment with a professional of the woman's choice, giving information on recovery, conceiving again and future fertility, and providing support contacts and a 24-hour contact [38]. The SRU lexicon documents that patients associate the word «failure» with blame [1]. The sources consulted do not quantify the psychological morbidity specific to anembryonic pregnancy.

3.6. Profile by type of chromosomal anomaly

The chromosomal anomaly determines the timing of loss and the ultrasound appearance. Lethal autosomal trisomies and tetraploidy are associated with early arrest and are proportionally more frequent in AP; monosomy X and triploidy allow initial embryonic development and are more frequent in miscarriages with an embryo [5]. In the Urumqi cohort, the risk of an anomaly was highest between 8 and 10 weeks, maternal age of 35 years or more was associated with more anomalies (odds ratio, OR, 1.72; 95% confidence interval, 95% CI, 1.31–2.26) and gestational age of 12 weeks or more with fewer (OR 0.27; 95% CI 0.21–0.34) [60]. In a Polish preprint of 400 losses (2023–2026, not peer reviewed), each additional week of gestational age reduced the probability of an abnormal result (OR 0.90; 95% CI 0.82–0.98) [89]. Diandric triploidy may be associated with very high hCG (80%) and a large placenta with a molar appearance [72].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Anembryonic pregnancy is suspected when a first-trimester scan shows an intrauterine gestational sac without a visible embryo. Suspicion is greater when the sac is large for the absence of an embryo, when dating is reliable and when a second scan shows no progression. NICE recommends informing the woman that diagnosis on a single scan is not 100% accurate, especially at very early gestational ages, and looking first for the heartbeat, measuring the CRL if there is an embryo and measuring the MSD only when there is no embryo [38]. Gestational age by last menstrual period should not be used alone to decide whether the heartbeat should already be visible [38]; long cycles and late ovulation explain many sacs «small for dates» that progress normally.

Suggestive but non-diagnostic findings are: CRL less than 7 mm without a heartbeat; MSD of 16 to 24 mm without an embryo; absence of an embryo with a heartbeat 7 to 13 days after a scan showing a sac without a yolk sac, or 7 to 10 days after a scan showing a sac with a yolk sac; absence of an embryo 6 weeks or more after the last menstrual period; empty amnion (amnion adjacent to the yolk sac without a visible embryo); enlarged yolk sac (greater than 7 mm); and small sac for the embryo (difference of less than 5 mm between MSD and CRL) [4]. A slow heart rate (less than 100 beats per minute at 5–7 weeks) and subchorionic haematoma are associated with loss but do not diagnose it; these findings justify reassessment in 7 to 10 days [4]. The SRU lexicon adds the calcified yolk sac and the expanded amnion sign, which on their own allow only the designation «concerning for early pregnancy loss» [1].

4.2. Emergency signs

Bleeding with haemodynamic instability and signs of infection require urgent uterine evacuation [4]. As a practical reference for the patient on expectant or medical management, ACOG considers excessive bleeding to be soaking two large pads per hour for two consecutive hours, in which case she should contact the service [4]. NICE asks the woman to contact the service if she has no bleeding within 48 hours of misoprostol [38], and WHO lists prolonged heavy bleeding, absence of bleeding with medical treatment, pain not relieved by medication and fever as reasons to return [43].

4.3. Pitfalls

An intrauterine sac without an embryo does not by itself confirm an intrauterine pregnancy. In ectopic pregnancy, an intrauterine fluid collection (pseudosac) may mimic an AP; the true gestational sac is an eccentric hypoechoic structure, with an intradecidual or double decidual sign, signs that are highly specific but not very sensitive [1, 38]. A 2026 report describes a 33-year-old woman at 9 to 10 weeks of gestation in whom an intrauterine pseudosac was interpreted as AP; curettage showed no villi, and laparotomy revealed a tubal abortion requiring salpingectomy [90]. Another report describes a submucous leiomyoma with complete cystic degeneration (65 × 45 mm) mimicking an empty sac in a 42-year-old woman with negative β-hCG [91]. A placenta with cystic spaces and very high hCG suggests a mole, but may correspond to an aneuploid hydropic miscarriage [84].

4.4. Screening

There is no population screening for anembryonic pregnancy and no relevant newborn screening. Prenatal aneuploidy screening by cfDNA in an ongoing pregnancy may be confounded by a second sac undergoing resorption (vanishing twin), by confined placental mosaicism (about 1% to 2% of CVS samples) or by low fetal fraction at early gestational ages; the test is more reliable from 10 weeks [92].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Ultrasound criteria

The diagnosis of anembryonic pregnancy is made by ultrasound and must have a specificity close to 100%, because treating a normal pregnancy misdiagnosed as a loss may terminate a wanted pregnancy or expose it to teratogenic drugs [4]. The 2013 SRU criteria (Doubilet and colleagues) [93], reproduced by ACOG for the woman with an intrauterine pregnancy of uncertain viability and kept unchanged in the 2024 SRU lexicon [1], are as follows [4, 93]:

The criteria favour specificity at the expense of sensitivity, because a false positive (diagnosing loss in a viable pregnancy) has more serious consequences than a delay of a few days in intervention. The SRU panel raised the CRL threshold from 5 to 7 mm and the MSD threshold from 16 to 25 mm for three reasons: the series that had set 5 mm and 16 mm were small, and a systematic review estimated 95% confidence intervals for specificity of 90% to 100% (CRL of 5 mm) and 88% to 100% (MSD of 16 mm); later series described embryos of 5 to 6 mm without a heartbeat and sacs of 17 to 21 mm without an embryo that went on to viable pregnancies; and interobserver variation is about ±15% for CRL and ±19% for MSD, so that 6 mm measured by one operator may correspond to 6.9 mm for another, and 21 mm to 25 mm. The time-based criteria rely on the reproducible chronology of development (sac at 5 weeks, yolk sac at 5.5 weeks, embryo with a heartbeat at 6 weeks, with a variation of about half a week); the date of the last menstrual period, in a spontaneous conception, is not reliable for a definitive diagnosis, and criteria based on slow growth of the sac or embryo proved unreliable. The suspicious signs (empty amnion, enlarged yolk sac, small sac) have been little studied and justify a follow-up scan in 7 to 10 days. Transvaginal ultrasound is the basis of the criteria; the transabdominal route alone is sufficient to diagnose loss only when an embryo with a CRL of 15 mm or more has no cardiac activity. The panel requires minimum quality standards: transvaginal assessment of the uterus and adnexa, transabdominal search for free fluid and a high pelvic mass, operators and physicians with training or certification in transvaginal ultrasound, and equipment suitable for the first trimester [93].

NICE, for the United Kingdom, follows a similar approach with a different decision design. Transvaginally, an MSD of less than 25.0 mm without an embryo requires a second scan at least 7 days later before any diagnosis; an MSD of 25.0 mm or more without an embryo requires a second opinion and/or a second scan at least 7 days later. For CRL, the threshold is 7.0 mm without a heartbeat, with the same rules. Transabdominally, the CRL or MSD is recorded and the scan repeated at least 14 days later. NICE adds that waiting for the repeat scan does not harm the outcome and that the woman should be given a 24-hour contact [38].

The evidence supporting these thresholds comes from prospective British cohorts. Abdallah and colleagues followed 1060 intrauterine pregnancies of uncertain viability in four London hospitals (462 without a yolk sac or embryo, 419 with a yolk sac without an embryo and 179 with an embryo without a heartbeat) until 11–14 weeks. The historical CRL threshold of 5 mm had 8.3% false positives, and 5.3 mm was needed to reach 0%; the MSD of 16 mm had 4.4% false positives, and 21 mm was needed for 100% specificity. Growth of the sac and embryo did not allow safe thresholds to be defined: MSD growth of 0.6 mm per day had a specificity of 90.1% (19 false positives), although CRL growth of less than 0.2 mm per day was always associated with miscarriage. Absence of a yolk sac or embryo on a second scan, performed 7 days or more after a scan showing an empty sac, was always associated with loss [4, 87].

Preisler and colleagues studied 2845 women in seven British early pregnancy units, with viability at 11–14 weeks as the outcome, and confirmed 100% specificity at the first scan for: MSD of 25 mm or more with an empty sac (364/364; CI 99.0–100%); CRL of 7 mm or more without cardiac activity (110/110; 96.7–100%); MSD of 18 mm or more without an embryo when the pregnancy was beyond 70 days (907/907; 99.6–100%); and CRL of 3 mm or more without cardiac activity beyond 70 days (87/87; 95.8–100%). At the repeat scan, the following had 100% specificity: an embryo without cardiac activity on two scans 7 days or more apart (103/103), absence of an embryo with an MSD of less than 12 mm that did not double in 14 days or more (478/478; 99.2–100%) and absence of an embryo with an MSD of 12 mm or more without a heartbeat after 7 days or more (150/150; 97.6–100%). The authors concluded that the adopted thresholds are appropriate but do not take gestational age into account, and that the repeat intervals in the guidance were still too liberal [94].

ACOG points out limitations of the SRU criteria: there are few cases close to the thresholds, and the 7-day interval used in the study became 14 days in the guideline without clear justification. It recommends that the decision be individualised with the patient, considering her wish to continue the pregnancy, her willingness to wait until there is absolute certainty and the consequences of waiting, such as unwanted spontaneous expulsion, unscheduled visits or anxiety [4].

5.2. Ultrasound signs of intrauterine pregnancy and normal chronology

The gestational sac is generally visible at 5 weeks, and the yolk sac at about 5.5 weeks, normally less than 6 mm. An intrauterine sac without a yolk sac or embryo should be described as a «probable gestational sac» or «probable pregnancy»; the intradecidual and double decidual signs are highly specific but not very sensitive. The first trimester extends to 13 weeks and 6 days [1]. In incomplete loss, an endometrial thickness of less than 10 mm has a high negative predictive value for retained tissue, and intracavitary vascularity increases the probability of tissue [1].

With current transvaginal ultrasound, the double decidual and intradecidual signs are absent in at least 35% of gestational sacs; therefore, in a woman with a positive pregnancy test, a round or oval intrauterine fluid collection without a yolk sac or embryo is most likely a gestational sac and only rarely a pseudosac or decidual cyst of an ectopic pregnancy, and the presence of a yolk sac or embryo makes it certain. The yolk sac measures about 3 to 5 mm when it appears, and the embryo appears next to it at about 6 weeks, already with a heartbeat [93].

5.3. hCG and pregnancy of unknown location

Serial hCG does not diagnose AP, but it is necessary when the location of the pregnancy has not been established. NICE recommends measurements 48 hours apart in pregnancy of unknown location: a rise of more than 63% indicates a probable developing intrauterine pregnancy, to be confirmed by ultrasound in 7 to 14 days (earlier if hCG is 1500 IU/L or more); a fall of more than 50% indicates a probable non-developing pregnancy, with a urine test 14 days later; and serum progesterone should not be used as an adjunct [38]. When an intrauterine pregnancy cannot be identified with certainty, ACOG recommends serial hCG and ultrasound before treatment, to exclude ectopic pregnancy [4]. An empty sac is a «probable pregnancy» and not a pregnancy of unknown location [1, 38].

The SRU panel analysed the value of a single hCG in pregnancy of unknown location. The discriminatory level (the value above which the sac of a normal pregnancy would always be visible) fell from 6500 IU/L, in the era of transabdominal ultrasound, to 1000 to 2000 IU/L with the transvaginal route, but there are documented viable pregnancies in which the embryo with a heartbeat only appeared on the follow-up scan, after a first scan without a sac with hCG above 2000 and even 3000 IU/L. With an empty uterus and hCG above 2000 IU/L, the most likely diagnosis is a non-viable intrauterine pregnancy, about twice as frequent as an ectopic; with data from one institution, the authors estimated the probability of a viable intrauterine pregnancy at about 2% with hCG of 2000 to 3000 IU/L and about 0.5% above 3000 IU/L, estimates they declare imprecise. They recommend not giving presumptive treatment for ectopic pregnancy (methotrexate, other drugs or surgery) to a haemodynamically stable woman with a single hCG of less than 3000 IU/L and, above that value, obtaining at least one follow-up hCG and scan before treatment. As hCG in ectopic pregnancy is often less than 1000 IU/L and does not predict rupture, clinical suspicion of ectopic pregnancy requires transvaginal ultrasound whatever the hCG [93].

5.4. Indications for genetic analysis of the products of conception

Guidelines diverge on when to study the tissue:

The divergence reflects different objectives. For ACOG, RCOG and ESHRE, the first loss is a frequent event whose investigation does not change management; for ASRM, an aneuploid result explains the loss, spares additional investigations and has prognostic value (section 8). ASRM states that a single euploid early miscarriage does not increase the risk of a second loss, which does not justify reflex investigation after an isolated euploid miscarriage [40]. A North American decision analysis, in a simulated cohort at the second miscarriage, showed that karyotyping the tissue and investigating recurrent loss only in euploid cases was less costly in all age groups (Monte Carlo simulation: 4498 ± 792 versus 5022 ± 1130 dollars) [95]. A 2026 review estimates about 23 million miscarriages per year worldwide and more than 90% without an established cause, because guidelines do not recommend routine analysis [96]. In a Polish tertiary centre, uptake of tissue testing rose from 10.7% in 2023 to about 20% in subsequent years, with microarray replacing QF-PCR and 54.3% of tests performed after the first miscarriage [89].

5.5. Tissue collection and transport

The tissue to be studied is the chorionic villi. After uterine aspiration, macroscopic separation of the villi reduces maternal contamination. In the case in section 10, the villi were placed in saline for DNA extraction and the remaining tissue in formalin for histology [84]. Karyotyping requires fresh, viable tissue, is not possible on formalin-fixed tissue and fails in 10% to 40% of samples through lack of growth [35, 40]; molecular methods work on fresh tissue and on paraffin blocks (CMA success rate of 92.4% on fresh tissue and 86.4% on formalin-fixed paraffin-embedded tissue, FFPE) [35]. ASRM accepts home collection of tissue after medical treatment [40]. WHO recommends that gestational tissue be handled like any other biological material, unless the woman requests another arrangement [43]. In the Polish preprint, villi were unavailable in 20.8% of cases [89]. In PCR-based analyses a maternal DNA sample should be available to exclude maternal cell contamination [77].

5.6. Techniques, yield and limitations

The meta-analysis by Dhillon and colleagues (2014), cited by the Oxford Desk Reference, compared conventional karyotyping with CMA in miscarriages: concordance of 86.0% (95% CI 77.0–96.0%); CMA detected 13% (95% CI 8.0–21.0%) additional anomalies relative to full karyotyping, karyotyping detected 3% (95% CI 1.0–10.0%) additional anomalies relative to CMA (for example, balanced translocations) and there were variants of uncertain significance in 2% (95% CI 1.0–10.0%) [3]. Molecular cytogenetic techniques have a higher success rate, faster reporting and a more robust analytical workflow [3]. Anomaly rates of 60% to 70% have been described with CMA on villi at the time of diagnosis and on samples that failed culture [3].

The technique determines which anomaly can be seen. A 69,XXX triploidy is missed by array-CGH or by CNV-seq without allelic information, and a 92,XXXX tetraploidy is missed by SNP-array; in the CMA triploidy series of Zheng and colleagues, 47.8% were 69,XXX, 43.5% 69,XXY and 4.3% 69,XYY [97]. A «normal female» result without exclusion of maternal contamination is not informative.

5.7. Maternal cell-free DNA after miscarriage

When there is no tissue (expulsion at home, tissue not preserved, culture failure), cfDNA from maternal plasma allows the loss to be studied. Circulating «fetal» DNA is trophoblastic and is present at normal concentration in AP [66]. Two 2025 meta-analyses summarise performance:

In an Italian series of 299 cfDNA samples in miscarriages between 7+0 and 14+6 weeks, mean fetal fraction was 5.83%, 77.3% of samples had a fetal fraction of 4% or more, and 56.3% of informative samples showed anomalies, mostly trisomy 16; in the 28 with CMA of the tissue, concordance was complete [67]. In the Danish COPL cohort (1463 women, 2020–2022), cfDNA and β-hCG fell after expulsion; median fetal fraction was 4.7% in the first 6 hours and 2.8% after 12 hours, and the proportion of inconclusive results rose from 9.1% with tissue in situ to 27.1% at 12–24 hours, with 30% inconclusive by the third day. Sampling should be done before expulsion or up to 12 hours afterwards [99]. In ongoing pregnancies, fetal fraction amplification allows cfDNA testing at 6–9 weeks (median fetal fraction 9.0% versus 18.5% from 10 weeks; failure 1.5%), demonstrating technical feasibility at very early gestational ages [100].

cfDNA does not distinguish confined placental mosaicism from an embryonic anomaly, does not reliably detect triploidy on all platforms and, in a multiple pregnancy with one sac undergoing resorption, may reflect the lost conceptus [92].

5.8. Histology and genotyping: distinguishing mole from hydropic miscarriage

When ultrasound suggests a mole or histology shows hydropic villi, p57 immunohistochemistry and STR genotyping distinguish the entities. p57 is expressed from the maternal allele: its absence in the cytotrophoblast and stroma indicates an androgenetic complete mole; its presence indicates tissue with a maternal contribution (diandric triploid partial mole, biparental hydropic miscarriage or biparental mole due to a maternal effect, in which p57 may be discordant). Genotyping compares the alleles of the tissue with those of maternal DNA and determines whether the conceptus is biparental diploid, androgenetic diploid or triploid [10, 84]. A biparental diploid mole suggests a maternal-effect cause and justifies testing NLRP7 and KHDC3L in the woman [10].

5.9. Report content and interpretation

The report of a study of the product of conception should state the tissue analysed (villi, membranes, embryonic tissue), its state of preservation, the technique and its resolution, whether maternal contamination was excluded (with comparison with maternal DNA, when performed), the result in ISCN nomenclature, the chromosomal sex, parental origin when determined and the classification of CNVs (pathogenic, likely pathogenic, of uncertain significance). A female euploid result without a maternal contamination study should be flagged as possibly maternal. Variants of uncertain significance in products of conception (2% in the Dhillon meta-analysis; 2% in the Zhao series) are reinterpreted only with parental segregation [3, 59]. A structural imbalance in the tissue (for example, a translocation derivative) justifies parental karyotyping, as already recommended by the 2011 RCOG guideline cited by the Oxford Desk Reference [3].

5.10. Algorithm

The following algorithm summarises the guidelines; the points on which they diverge are shown in section 5.4.

5.11. Prenatal and preimplantation diagnosis in a subsequent pregnancy

In a pregnancy following a sporadic aneuploid loss, prenatal diagnosis follows the indications for the general population and for maternal age. The meta-analysis by Akolekar and colleagues (2015), cited by the Oxford Desk Reference, found a risk of miscarriage before 24 weeks of 0.81% (95% CI 0.58–1.08%) after amniocentesis and 2.18% (95% CI 1.61–2.82%) after CVS, versus 0.67% and 1.79% in controls, with a procedure-attributable risk of 0.11% (95% CI −0.04 to 0.26%) for amniocentesis and 0.22% (95% CI −0.71 to 1.16%) for CVS; for counselling, about 1% is used for CVS and 0.5% for amniocentesis. CVS is performed from 11 weeks and amniocentesis from 15–16 weeks; early amniocentesis (before 13 weeks) increased losses and talipes in the CEMAT study and has been abandoned [77]. Preimplantation genetic testing applies to carriers of balanced rearrangements.

6. Differential Diagnosis

The differential diagnosis has two levels: the ultrasound level (what may look like an empty sac) and the genetic level (which cause explains the loss and which carries a risk of recurrence).

6.1. Ultrasound differential diagnosis

The first differential is a misdated normal pregnancy. The diagnostic criteria were designed not to terminate viable pregnancies, and any sac with an MSD of less than 25 mm without an embryo requires a repeat scan [4, 38]. The second is ectopic pregnancy: an intrauterine sac without a yolk sac or embryo should be described as a «probable pregnancy» and interpreted together with serial hCG and repeat ultrasound; histology without villi after curettage requires exclusion of an ectopic [1, 90]. Rare cystic uterine lesions, such as leiomyoma with cystic degeneration, may mimic a sac, and a negative β-hCG points the way [91].

6.2. Hydatidiform mole and hydropic miscarriage

The complete mole shares the absence of an embryo with AP, but is androgenetic, whereas AP trophoblast is biparental [48]. The complete mole is 46,XX of paternal origin in 90% of cases; the partial mole is diandric triploid in 90% to 93% and usually has embryonic or fetal tissue, villi of variable size with focal oedema, cavitation and trophoblastic hyperplasia [72]. Persistent trophoblastic disease occurs, in the United Kingdom, after 15% of complete moles and 0.5% to 1% of partial moles, and choriocarcinoma after up to 3% of complete and about 0.1% of partial moles [72]. The case in section 10 shows that a diploid aneuploid miscarriage may mimic a partial mole on ultrasound and clinically, and that the distinction depends on genotyping and p57; post-molar follow-up applies only to a proven mole [84]. The androgenetic origin of the complete mole was demonstrated by Kajii and Ohama in 1977; about 90% of complete moles are homozygous, through duplication of a haploid sperm, and the rest result from fertilisation of an anucleate oocyte by two sperm, and about 25% of clinically diagnosed moles are partial [12].

6.3. Recurrent mole and maternal-effect genes

In a healthy woman with biallelic variants in NLRP7 (HYDM1) or KHDC3L (HYDM2), conceptions are abnormal and without an embryo, with excessive trophoblastic proliferation and cystic degeneration of the villi; miscarriages, stillbirths and growth restriction also occur. The moles of these women are characteristically biparental diploid (all of them in a review of 123 molar tissues), unlike the androgenetic sporadic complete mole. Biallelic variants in NLRP7 or KHDC3L explain 50% to 80% of recurrent moles, with NLRP7 as the main gene; KHDC3L explains 10% to 14% of NLRP7-negative patients [10, 11]. OMIM describes familial recurrent mole as an autosomal recessive disorder in which the losses include, in addition to complete moles, partial moles, stillbirths, ectopic pregnancies, early neonatal deaths and miscarriages, some of which may be undiagnosed moles. In a review of 150 products of conception from 75 women with NLRP7-associated moles, all but 3 were biparental diploid; the remaining 3 were triploid, 2 of them digynic, and one resulted from non-extrusion of the second polar body; digynic triploid moles have also been described in women with biallelic KHDC3L variants. Severity depends on the type of variant: truncating NLRP7 variants are associated with absent expression of p57 (CDKN1C), absence of embryonic tissue and excessive trophoblastic proliferation, whereas some missense variants allow partial embryonic differentiation and are associated with late miscarriages with a formed fetus, stillbirths, early neonatal deaths or live births. Men with two NLRP7 variants have no described reproductive problems. OMIM also lists a provisional autosomal dominant phenotype (OZEMA25) associated with paternally inherited heterozygous NLRP7 variants in two Chinese women with embryonic developmental arrest; one of the two variants was later reclassified as of uncertain significance because of its population frequency (9.5% of alleles in the gnomAD v4.1.0 population database), and a study of 24 women with a mean of 4.7 miscarriages of unknown cause found no pathogenic NLRP7 variants [12–15]. In the series that gave rise to the OZEMA25 entry, the five women described had normal menstrual cycles and sex hormones, but their IVF embryos arrested early and almost never reached the blastocyst stage, and the few transferred did not implant; screening of 178 Chinese women with early embryonic arrest added three carriers of other heterozygous NLRP7 missense variants, without segregation studies, and the mouse oocyte model showed abnormalities of the spindle, chromosome alignment and organelle distribution [20].

Not all recurrent moles of maternal cause are biparental. In women without NLRP7 or KHDC3L variants, exome sequencing identified biallelic variants in female meiosis genes whose moles are complete, diploid and monospermic androgenetic, the same genotype as the sporadic complete mole. In a study of 65 women with recurrent moles, miscarriages and infertility, negative for the two main genes, five had biallelic variants in three genes involved in the formation of DNA double-strand breaks in meiosis: two in MEI1 (HYDM3, 22q13.2) and two in C11orf80, also designated TOP6BL (HYDM4, 11q13.2) [16, 17]. In one of the MEI1 families, the proband had four miscarriages followed by four complete moles, all spontaneously conceived, and one unsuccessful ICSI cycle; two sisters homozygous for the same nonsense variant had only miscarriages, and none of the three had a live birth; in the other family, the brother with the same combination of variants had non-obstructive azoospermia without Y chromosome microdeletions. The molar tissues of these probands were diploid on flow cytometry, without nuclear p57 expression, monospermic androgenetic on microsatellite genotyping and without aneuploidies on SNP microarray [16]. In OMIM, MEI1 is also associated, in women, with early embryonic arrest with implantation failure (OZEMA26, OMIM 621620) and, in men, with spermatogenic arrest (SPGF103, OMIM 621619); two compound heterozygous Chinese sisters had recurrent moles, one of them also after assisted reproduction, but one of the two variants did not reduce protein expression and is present at low frequency in the population [16]. For C11orf80/TOP6BL, the two homozygous women (one with a miscarriage and two moles, the other with three complete moles from two different partners) had no children; one of the variants affects a conserved residue required for interaction with SPO11, a protein essential for double-strand break formation in the mouse [17]. In a later cohort of 75 women with recurrent moles without variants in the genes then known, biallelic variants were identified in HFM1 (HYDM5, 1p22.2; provisional association, in a single consanguineous Iranian family with two sisters and a maternal aunt affected and a monospermic androgenetic complete mole confirmed by genotyping) and in KASH5 (HYDM6, 19q13.33; a Jordanian woman with three moles and two miscarriages, with no tissue available for genotyping) [18, 19]. In Hfm1-null mice, oocytes do not complete synapsis of homologous chromosomes or form crossovers, the follicular reserve is depleted early and, in meiosis, oocytes frequently extrude all chromosomes into the polar bodies; this behaviour is compatible with the formation of an oocyte without a maternal genome which, after fertilisation, gives rise to an androgenetic mole [18]. In 2026 a 28-year-old Egyptian woman homozygous for a KASH5 missense variant was described, whose two complete moles progressed to gestational trophoblastic neoplasia: the first required a second curettage, methotrexate with folinic acid and then actinomycin D, with remission at 25 weeks; the second presented as an invasive mole on ultrasound follow-up and was treated with methotrexate for 6 weeks; according to the patient, a sister with three miscarriages and two moles died of metastatic mole, with no clinical records available, and one of the moles of the Jordanian patient had also progressed to neoplasia [19]. These four forms rest on few families, with transmission compatible with autosomal recessive inheritance, and the number of patients described does not allow penetrance or the risk of trophoblastic neoplasia by genotype to be estimated [16–19].

The maternal-effect genes associated with multilocus imprinting disturbances (NLRP2, NLRP5, NLRP7, PADI6, KHDC3L) cause pregnancy losses, molar pregnancy or apparent infertility in mothers with biallelic variants, with exact risks unknown; the three-generation pedigree should ask about infertility, multiple miscarriages and moles in female relatives [33].

6.4. Structural and parental causes

A structural imbalance in the tissue raises the possibility of a parent carrying a translocation. In more than 22,000 Quebec couples with two or more miscarriages, 4.7% had a member carrying a rearrangement (mostly reciprocal or Robertsonian translocations), versus 0.5% in the population; Barber and colleagues found 406 balanced rearrangements in 20,432 parents with recurrent miscarriages (1.9%) and questioned the value of parental karyotyping after observing only four subsequent imbalances detected prenatally [3]. In the series of Carp and colleagues of 1108 patients with recurrent loss, chromosomal aberrations occurred in 23.2% of miscarriages of couples without a parental aberration and in 30.8% of those of couples with a parental aberration (OR 1.47; 95% CI 0.63–3.39), and only 4 of 39 had an unbalanced translocation [102].

6.5. Diagnoses that should not be mistaken for a cause

A chromosomal heteromorphism found in the parents does not explain the loss. Baghbani and colleagues described a couple with four anembryonic pregnancies and 9qh heteromorphism in both partners and suggested an association [103]; 9qh heteromorphism is a population variant with no demonstrated effect on reproduction, and the case illustrates a non-causal finding. Likewise, hereditary thrombophilia is not consistently associated with early loss; only antiphospholipid syndrome has a demonstrated association [4].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no treatment that corrects the chromosomal cause of an anembryonic pregnancy; the anomaly lies in the conceptus and is, in most cases, sporadic. Management aims to complete uterine evacuation safely, respecting the woman's preference, and to decide whether the tissue should be studied. The three options (expectant, medical and surgical) result in complete evacuation in most patients, and serious complications are rare and comparable [4]. WHO recommends that the choice between expectant, medical or surgical management of missed abortion before 14 weeks be based on the clinical condition and the woman's preference, and that expectant management be offered after informing her that expulsion takes longer and that the risk of incomplete evacuation is greater [43]. No intervention prevents early loss: pelvic rest, vitamins, uterine relaxants, hCG and bed rest have shown no benefit [4].

Before any treatment, the diagnosis must meet the criteria in section 5, because treating a normal pregnancy may terminate it or cause malformations [4]. Misoprostol given in a pregnancy that continues is associated with skull defects, cranial nerve palsies and facial and limb malformations [104].

7.2. Expectant management

NICE recommends expectant management for 7 to 14 days as first line, except when there is a higher risk of haemorrhage (for example, at the end of the first trimester), a previous traumatic experience associated with pregnancy, coagulopathy or refusal of transfusion, or signs of infection; it recommends a urine pregnancy test 3 weeks later [38]. ACOG states that, given sufficient time (up to 8 weeks), expectant management achieves complete expulsion in about 80% of women, with greater effectiveness in symptomatic women and in incomplete loss than in missed abortion and anembryonic pregnancy, and limits it to the first trimester, owing to the lack of safety studies and the risk of haemorrhage in the second [4]. The woman should receive information about moderate to heavy bleeding and cramps, a prescription for analgesics, instructions on when and whom to call and an indication that surgery may be needed if expulsion is not complete [4]. The most widely used criterion for complete expulsion is absence of a gestational sac with an endometrial thickness of less than 30 mm; a thick endometrium in an asymptomatic woman does not require surgery [4].

7.3. Medical treatment

7.3.1. Recommended regimens

Between 13 and 17 weeks, FIGO recommends, in missed abortion, oral mifepristone 200 mg and, 1 to 2 days later, misoprostol 400 µg every 3 hours by the buccal, sublingual or vaginal route until expulsion [105]. FIGO notes that the sublingual and oral routes have more adverse effects, that the vaginal route should be avoided if there is vaginal bleeding, that misoprostol is safe before 28 weeks even with a previous caesarean section, that missed abortion before 12 weeks can be self-managed at home and that routine aspiration after medical treatment is not necessary [105].

Sources diverge on the interval between mifepristone and misoprostol: 24 hours in ACOG and the PreFaiR trial, 48 hours in NICE and the MifeMiso trial, 1 to 2 days in WHO, FIGO and the Society of Obstetricians and Gynaecologists of Canada (SOGC). They also diverge on repeat misoprostol: one repeat after 3 hours or more in ACOG, a single dose in NICE, repetition every 3 hours from 10 weeks in FIGO. In a secondary analysis of PreFaiR, success was 96.6% when misoprostol was taken 7 to 20 hours after mifepristone, versus 54.6% between 0 and 6 hours and 87.5% between 21 and 48 hours, but these are exploratory data [107]. SOGC mentions some evidence of equivalent efficacy with misoprostol 10 hours after mifepristone [106]. Trial NCT07506512, not yet recruiting, will compare intervals in 1000 women [108].

7.3.2. Mifepristone

Mifepristone is an antiprogestogen that blocks the progesterone receptor, sensitises the myometrium to prostaglandins and softens the cervix. In Portugal it is authorised as Mifegyne® 200 mg tablets (Exelgyn; decentralised procedure NL/H/2937/002; authorised 16/02/2009, renewed 17/01/2011), a medicine subject to restricted medical prescription for exclusive hospital use, subject to additional monitoring, not reimbursed [109]. In the United States it is approved as Mifeprex® (Danco, NDA 020687, 28/09/2000) and as generics (GenBioPro, ANDA 091178; Evita Solutions, ANDA 216616, approved 30/09/2025), only through the risk evaluation and mitigation strategy (REMS) programme [110]. In Brazil, it is not registered with the National Health Surveillance Agency (ANVISA) [111]. Korlym® (300 mg) is mifepristone for Cushing's syndrome and does not apply [110].

The reference dose in early loss is 200 mg orally, as a single dose, 24 to 48 hours (WHO: 1–2 days) before misoprostol [4, 38, 43]. No label includes early pregnancy loss as an indication, and use is off-label. For comparison, the US label for medical termination up to 70 days indicates 200 mg on day 1 followed, 24 to 48 hours later, by buccal misoprostol 800 µg (four 200 µg tablets, two in each cheek for 30 minutes), with possibly lower efficacy if the interval is less than 24 or more than 48 hours [110]. The Portuguese summary of product characteristics (SmPC) indicates, for termination up to 49 days of amenorrhoea, 600 mg as a single dose followed, 36 to 48 hours later, by oral misoprostol 400 µg or vaginal gemeprost 1 mg (alternative: 200 mg with gemeprost), between 50 and 63 days 600 mg or 200 mg with gemeprost 1 mg, for cervical preparation before surgical termination 200 mg 36 to 48 hours beforehand, and for fetal death in utero 600 mg daily for two days; if vomiting occurs within 45 minutes, the dose is repeated, and with cytochrome P450 3A4 (CYP3A4) inducers 600 mg is used [109]. The 200 mg dose of the early-loss guidelines differs from the 600 mg dose in the Portuguese SmPC for early termination and lies outside the label conditions.

Contraindications common to all indications, in the Portuguese SmPC, are chronic adrenal insufficiency, hypersensitivity, severe uncontrolled asthma and hereditary porphyria; for termination of pregnancy, pregnancy not confirmed by ultrasound or laboratory tests, gestation beyond 63 days and suspected extrauterine pregnancy [109]. The US label adds ectopic pregnancy or undiagnosed adnexal mass, long-term corticosteroid therapy, haemorrhagic disorders or anticoagulation and an intrauterine device (IUD) in situ, and carries a boxed warning for serious infections (for example, with Clostridium sordellii, with possible sepsis without fever) and haemorrhage, rare and sometimes fatal, with no established causal link [110]. Mifepristone inhibits CYP3A4 [109]. The Portuguese SmPC requires Rh factor determination and prevention of isoimmunisation in medical termination and immediate initiation of contraception [109]; current recommendations on anti-D immunoglobulin before 12 weeks diverge from this requirement (section 7.6).

7.3.3. Misoprostol

Misoprostol is a synthetic prostaglandin E1 analogue that causes uterine contractions and cervical ripening. In Portugal it is authorised as Cytotec® 0.2 mg (Laboratórios Pfizer) with exclusively gastroduodenal indications (prevention and treatment of lesions due to non-steroidal anti-inflammatory drugs, NSAIDs, active gastric or duodenal ulcer, erosive gastroduodenitis; 400–800 µg per day in 2 to 4 doses) and is contraindicated in pregnancy; Arthrotec® combines diclofenac and misoprostol. There is no misoprostol for gynaecological use authorised and marketed in Infomed, so its use in pregnancy loss is outside the SmPC indication [112]. In the United States, Cytotec® (Pfizer, NDA 019268, 27/12/1988) is approved only to reduce the risk of NSAID-induced gastric ulcer (200 µg 4 times daily with food), with a boxed warning about birth defects, abortion, preterm birth and uterine rupture when given to pregnant women, a risk that increases with gestational age and with previous uterine surgery, including caesarean section [104].

In Brazil, obstetric misoprostol is registered as Prostokos® (Infan Indústria Química Farmacêutica Nacional, registration 115570044, active status, class «other products for use in gynaecology and obstetrics»), and the Cytotec® registration is inactive [111]. The Prostokos® package insert, restricted to hospital use, presents vaginal tablets of 25, 100 and 200 µg and indicates it for termination of pregnancy at or near term, induction of labour with a dead fetus before 30 weeks and legal abortion; for legal abortion it indicates 1 tablet of 200 µg every 6 hours vaginally. The insert contraindicates the drug with a uterine scar, previous caesarean section, cerebrovascular disease, coronary disease, NSAIDs in the previous 4 hours and hypersensitivity [113]. Anembryonic pregnancy and first-trimester missed abortion are not among the indications in the insert; use is off-label, and the reference dose is that of the guidelines (800 µg). The insert's contraindication in previous caesarean section diverges from the FIGO note, which considers misoprostol safe before 28 weeks with a previous caesarean section [105, 113].

The reference dose in anembryonic pregnancy is 800 µg (vaginal, buccal or sublingual), after mifepristone or alone [4, 38, 43]. Higher doses are more effective than lower ones, and the vaginal and sublingual routes more effective than the oral, although the sublingual route causes more diarrhoea [4]. In the North American National Institute of Child Health and Human Development (NICHD) trial, 800 µg vaginally achieved complete expulsion by day 3 in 71% of women and in 84% after a second dose, when needed [4]; in a secondary analysis of 473 women, heavy bleeding after the first dose and an open cervix were predictors of success by day 3 (84% with one or both), and absence of both by day 8 was associated with 94% failure [114]. Misoprostol was associated with more haemoglobin falls of 3 g/dL or more than aspiration, but rates of admission or transfusion for haemorrhage were similar (0.5% to 1%) [4].

The expected effects are bleeding heavier than a menstrual period and cramps that are sometimes severe, which the woman should know about before treatment, including the volume of bleeding that requires contact; the sublingual route causes more diarrhoea, and the sublingual and oral routes have more adverse effects [4, 105]. NICE recommends offering analgesia and antiemetics [38], and WHO recommends that analgesia always be available, given in advance or provided for use at home [43]. In the PreFaiR trial, pretreatment with mifepristone concentrated moderate to heavy bleeding on the day of misoprostol (73% versus 47%), increased the proportion of patients with light or no bleeding on days 4 to 8 (78% versus 61%) and was associated with slightly greater mean pain on days 2 to 4 (6.9 versus 6.0) [115].

7.3.4. Letrozole (investigational)

Letrozole is an aromatase inhibitor authorised for breast cancer and used off-label for ovulation induction; in pregnancy loss, its use is experimental and off-label. WHO suggests, for medical termination before 12 weeks, oral letrozole 10 mg daily for 3 days followed by sublingual misoprostol 800 µg on the fourth day, with low to very low certainty evidence versus misoprostol alone, and considers that the regimens for termination before 12 weeks may be applied to missed abortion [43]. Application to missed abortion is an extrapolation. A 2026 meta-analysis of 12 trials (1524 women; medical termination and medical management of miscarriage) found a higher rate of complete abortion with letrozole plus misoprostol than with misoprostol alone (relative risk, RR, 1.45; 95% CI 1.25–1.68; I² 73%), with high heterogeneity [116]. In an Egyptian trial of 225 women with first-trimester missed abortion, cumulative complete abortion by day 7 was 76.0% with letrozole plus misoprostol, 53.5% with misoprostol and 62.5% with letrozole alone (p = 0.0005); the combination had more bleeding (85.3%) and pain (92.0%) [117].

7.4. Surgical treatment

Uterine aspiration (electric or manual) is superior to sharp curettage, and additional sharp curettage after aspiration brings no benefit (level B); success approaches 99% [4]. NICE offers manual vacuum aspiration under local anaesthesia in an outpatient setting or evacuation in theatre under general anaesthesia [38]. Surgical evacuation is urgent in the presence of haemorrhage, haemodynamic instability or infection, and preferable with severe anaemia, bleeding disorders or cardiovascular disease; many women prefer it because it completes the process immediately and requires less follow-up [4]. Surgery in theatre is the most expensive option, and office aspiration may be more cost-effective [4]. Up to 12 weeks, FIGO does not consider cervical preparation before aspiration necessary (consider misoprostol 400 µg 1 to 2 hours beforehand in adolescents aged 17 years or under) [105]. Aspiration allows collection of villi in good condition for genetic study (section 5.5).

Antibiotic prophylaxis should be considered for aspiration for early loss; ACOG recommends a single preoperative dose of doxycycline (some experts use 200 mg 1 hour before surgery; level C) [4]. WHO recommends appropriate prophylactic antibiotics before or during surgery, regardless of the risk of pelvic inflammatory disease, and recommends against their use in medical treatment [43]. For pain, WHO recommends routinely offering analgesia (for example, NSAIDs), recommends paracervical block for aspiration before 14 weeks, suggests offering conscious sedation combined with the block when available and recommends against routine use of general anaesthesia [43].

The late risks of curettage are relevant to the choice. In a meta-analysis of 21 observational studies (1,853,017 women), previous curettage was associated with preterm birth before 37 weeks (OR 1.29; 95% CI 1.17–1.42), before 32 weeks (OR 1.69; 1.20–2.38) and before 28 weeks (OR 1.68; 1.47–1.92), and the comparison with medical treatment gave OR 1.19 (1.10–1.28); multiple curettages increased the risk (OR 1.74; 1.10–2.76) [118]. In another meta-analysis of 912 women with hysteroscopy up to 12 months after miscarriage, intrauterine adhesions occurred in 19.1% (95% CI 12.8–27.5%), mostly mild (58.1%), and the number of curettages was the main risk factor; reproductive outcomes were similar between expectant, medical and surgical management, with limited data [119]. Observational studies do not exclude confounding.

7.5. Follow-up after treatment

ACOG recommends documenting complete expulsion by ultrasound in 7 to 14 days, or by serial β-hCG when ultrasound is not available, also taking into account the symptoms reported by the patient [4]. NICE recommends a urine pregnancy test 3 weeks after medical treatment or expectant management; a positive test requires exclusion of retained tissue, a mole or ectopic pregnancy [38]. WHO considers that there is no medical need for a routine follow-up visit after uncomplicated medical or surgical abortion, provided the woman is informed of the signs that justify returning [43].

7.6. Anti-D immunoglobulin

Prevention of RhD alloimmunisation before 12 weeks is the point of greatest divergence between recent guidelines:

WHO justified its recommendation with a systematic review that found only two eligible studies, both from 1972 (Israel and the United States), with very low certainty evidence; although fewer treated women formed antibodies, the panel considered resources, cost-effectiveness and feasibility and extended the limit from 9 to 12 weeks [43]. SMFM reads the same scarcity of data in the opposite direction [124]. As cited by Wong and Paulson, the 2024 ACOG update is based on the lack of conclusive evidence of benefit and on the delay or barrier to abortion caused by additional in-person visits for Rh testing and injection, and records that WHO, the Royal College of Obstetricians and Gynaecologists (RCOG), SOGC, SFP and the National Abortion Federation (NAF) no longer recommend prophylaxis in abortion before 12 weeks [122]; the CNGOF table places the SOGC and NAF positions in 2024 and restricts them to induced abortion [123]. None of the secondary sources read describes the position of the ACOG update on ectopic pregnancy or mentions a dose. In practice, a unit following NICE, WHO, CNGOF or the 2024 ACOG update does not routinely give anti-D to an RhD-negative woman with an anembryonic pregnancy managed before 12 weeks; one following SMFM offers it, and the 2018 ACOG text, which recommended it in surgical evacuation, has been superseded on this point [4, 120, 121].

The evidence base analysed by CNGOF is scant [123]. The only randomised trial, from 1972, compared 19 women with spontaneous miscarriage treated with anti-D (14 with surgical management) and 38 controls (34 with surgical management), between 8 and 24 weeks, and recorded no immunisation in either group, with insufficient power; two other intervention studies have recruitment, selection and detection biases. The population study by Wiebe and colleagues compared Canada, which gives anti-D in any abortion, with the Netherlands, which does not give it before 10 weeks in spontaneous miscarriage or before 7 weeks in induced abortion: the estimated prevalence of clinically significant red cell antibodies at early pregnancy screening was 4.21/1000 (95% CI 4.12–4.30) in Canada and 4.03/1000 (95% CI 3.93–4.12) in the Netherlands, with no possibility of causal inference and with populations not strictly comparable [123]. Secondary sources read this result differently: Wong and Paulson describe it as showing no clinically or statistically significant difference [122], whereas the systematic review by Gemzell-Danielsson and colleagues reports a statistically lower prevalence in the Netherlands [125]. A prospective multicentre North American study (2019–2022, published in 2023) quantified fetal red cells by flow cytometry in 506 women undergoing medical or surgical abortion before 12 weeks: three had, before the procedure, values above the threshold of 125 fetal red cells per 5 million adult red cells, which is not universally agreed, and none of the others exceeded this threshold after the procedure (0%; 95% CI 0–0.59%); the median increase was 0 fetal red cells per 5 million and previous bleeding was not associated with higher values (RR 1.06; 95% CI 0.84–1.36) [123]. CNGOF considers these data extrapolable to spontaneous miscarriage, but not to ectopic pregnancy [123]. The systematic review by Gemzell-Danielsson and colleagues (44 publications from 2003 to January 2024, 27 of them national or international guidelines) documented marked variability between countries and concluded, as expert opinion, in favour of alignment with the WHO 12-week limit [125].

In anembryonic pregnancy, the biological argument is particular. Fetal red cells express the RhD antigen from approximately 6 weeks, and primitive haematopoiesis begins in the yolk sac at around 4 weeks; on this basis, Wong and Paulson, in an opinion commentary and not a guideline, argue that anti-D is unnecessary in biochemical pregnancy and in anembryonic pregnancy, in which there is no embryonic haematopoiesis [122]. Applying this rule requires ultrasound confirmation of the diagnosis by the criteria in section 5. Adherence to the new guidance is uneven: in a survey of members of the Society for Reproductive Endocrinology and Infertility (SREI), conducted in November and December 2024 (140 responses from 812 invitations, 17.2%), 65.7% recommended anti-D for RhD-negative women with medically managed miscarriage, 70.0% with surgical management and 61.9% in ectopic pregnancy, 59.0% had no anti-D available in the clinic and only 7.9% correctly identified the 2024 ACOG recommendation [121]. The shortage of anti-D immunoglobulin, a plasma derivative obtained by apheresis from donors, is one of the arguments invoked for reducing its use in the first trimester [122, 126]. In Brazil, Gama Anti-D Grifols® and KamRho-D® have active ANVISA registrations; Rhophylac®, Partogama®, Matergam®, Rhesonativ® and Immunorho® are inactive [111]. The presentations authorised in Portugal were not consulted.

7.7. Progesterone

Progesterone has no indication in a diagnosed anembryonic pregnancy. The PRISM trial (4153 women with bleeding in early pregnancy, 48 British hospitals) compared vaginal progesterone 400 mg twice daily until 16 weeks with placebo and showed no significant overall benefit (live births at 34 weeks or more: 75% versus 72%; RR 1.03; 95% CI 1.00–1.07; p = 0.08) [127]. NICE recommends vaginal micronised progesterone 400 mg twice daily for women with a confirmed intrauterine pregnancy, bleeding and a previous miscarriage, continued until 16 completed weeks if there is a heartbeat; this indication ceased to be off-label in the United Kingdom in June 2025 [38]. The recommendation presupposes an ongoing pregnancy and does not apply to AP or after mifepristone.

7.8. Hydatidiform mole

When the tissue shows a complete or partial mole, initial management is uterine evacuation, followed by hCG surveillance in all women; in the United Kingdom, persistent trophoblastic disease is treated with chemotherapy adjusted to the FIGO score, with cure in more than 98% of registered cases [72]. In women with recurrent mole due to a maternal effect, each molar pregnancy requires aspiration, histopathology with genetic analysis of the tissue and serial serum hCG until undetectable, with methotrexate as first line in persistent trophoblastic disease [10].

7.9. Regulatory framework

In the United States, mifepristone used in pregnancy loss is subject to the same REMS as in elective termination, and this programme is under review. In a court filing of 07/10/2026 (Louisiana v. FDA), the federal authorities reported that FDA is conducting a mifepristone safety study in the Sentinel system, with about 100,000 women per group, results expected in mid-December 2026 and a report by March 2027, and that it is re-evaluating the REMS, including petitions to restore in-person dispensing; the court had denied the injunction and stayed the case on 07/04/2026, and the current generic label (06/06/2026) retains the indication and the REMS [110, 128].

7.10. Trials and comparative studies

These trials do not allow indirect comparisons with one another: primary outcomes, assessment intervals and populations (isolated anembryonic pregnancy, missed abortion with or without an embryo, incomplete loss) differ. The relative gain from mifepristone in PreFaiR (RR 1.25) corresponds to an absolute difference of about 17 percentage points in single-dose success, and in MifeMiso to an absolute reduction of 7 points in failure to expel and 8 points in surgery; the MifeMiso economic evaluation estimated an absolute difference in success of 6.6% (95% CI 0.7–12.5%) and a saving of 182 pounds per successfully treated miscarriage [133]. In MIST, societal costs per woman were 1086 pounds for expectant, 1410 for medical and 1586 for surgical management [134]. In the Cochrane network, heterogeneity by type of miscarriage may make the main analysis unreliable, and surgical and medical methods appear more beneficial in missed than in incomplete miscarriage [132]. Negative or discontinued trials include MiMi (Boston University, mifepristone plus misoprostol versus misoprostol, terminated in 2008 with 16 women), a trial of isosorbide mononitrate plus misoprostol in AP withdrawn without participants and a pilot trial of ulipristal plus misoprostol with 3 participants [108].

7.11. Developments in the last 12 months

The changes with practical effect between October 2025 and October 2026 concern guidelines and regulation. On 17/06/2026, NICE stopped recommending anti-D immunoglobulin before 12 weeks (guideline update) [38]. On 29/04/2026, ASRM published a committee opinion recommending that genetic testing of the tissue be offered from the second miscarriage (society opinion) [40]. On 30/09/2025, FDA approved a new mifepristone generic and modified the REMS, and has a safety study under way with results expected in December 2026 (ongoing regulatory process, documented in a primary court source) [110, 128]. In research, meta-analyses and cohorts on maternal cfDNA after miscarriage (diagnostic accuracy studies) [42, 67, 99], exome series in euploid products of conception (observational studies) [60, 78, 80], the Intolerome database (curated resource) [81], a review of maternal predisposition to aneuploidy [6] and a meta-analysis of letrozole plus misoprostol (heterogeneous randomised trials) [116] were published. Among registered trials, NCT06452719 (letrozole plus misoprostol, phase 2, 19 participants, University of Pennsylvania) ended on 16/04/2026 without results posted in the registry, and NCT07506512 (optimal interval between mifepristone and misoprostol, phase 3, 1000 participants) is not yet recruiting, with a planned start in July 2027 [108].

There are no interventional trials targeting the chromosomal cause of AP; the registered genomic studies are observational and focused on recurrent loss or mole [108].

7.12. Special situations, contraception and conceiving again

There are no data justifying delaying a new conception after an early loss; abstinence from vaginal intercourse for 1 to 2 weeks after complete expulsion is usually advised to reduce the risk of infection, without an evidence base [4]. Hormonal contraception may be started immediately, and an IUD may be inserted immediately after aspiration if septic abortion is not suspected (expulsion at 6 months of 5% versus 2.7% with insertion 2 to 6 weeks later) [4]. The mifepristone SmPC recommends starting contraception immediately [109]. Mifepristone is contraindicated with an IUD in situ, long-term corticosteroid therapy, anticoagulation or haemorrhagic disorders and porphyria [109, 110]; in these situations, and in severe anaemia, cardiovascular disease or coagulopathy, aspiration is preferable [4]. In adolescents, FIGO accepts misoprostol 400 µg 1 to 2 hours before aspiration at 17 years or under [105]. The sources consulted do not address lactation during treatment of an early loss.

8. Reproductive Options and Family Counselling

8.1. Key counselling messages

Counselling after an anembryonic pregnancy or a sporadic early loss rests on three facts. Loss is frequent and, in about half of cases, results from a chromosomal anomaly of the conceptus that arose by chance, unrelated to anything the woman did or did not do [4]. Most women have a successful subsequent pregnancy: 95% of women with subclinical loss in the Wilcox cohort achieved a clinical pregnancy within two years [34]. The risk of a further loss depends mainly on maternal age and the number of previous losses [3, 86].

8.2. Recurrence risk by scenario

Warburton and colleagues analysed 273 women with two karyotyped miscarriages in New York and Honolulu, with logistic regression adjusted for maternal age and site, and concluded that, after miscarriages with trisomies that are always lethal in utero, or after several early miscarriages with normal parental karyotypes, no increased risk of chromosomal anomaly is expected in future pregnancies; the hypothetical exception would be a recurrence restricted to one or a few chromosomes, for example through parental mosaicism [9]. Boué and colleagues had concluded that recurrence of miscarriage is influenced mainly by the couple's reproductive history before the karyotyped miscarriage [46]. Robinson and colleagues found age-related meiotic errors even in couples with repeated aneuploid miscarriages [3]. An aneuploid result therefore has a relatively favourable prognostic value: it explains the loss and does not indicate a persistent parental cause.

8.3. Maternal age and risk of aneuploidy in a subsequent pregnancy

The risk of aneuploidy in a subsequent pregnancy is that of maternal age. The table of Morris and colleagues (2002), reproduced in the Oxford Desk Reference, gives the probability of a live birth with Down syndrome by maternal age at delivery [8]:

The values refer to live births; the risk at the time of CVS or amniocentesis is higher, because about 43% of pregnancies with trisomy 21 are lost between CVS and term and about 23% between amniocentesis and term. The overall risk of any aneuploidy (trisomies 21, 18 and 13, 47,XXX and 47,XXY, age-dependent, and 45,X, 47,XYY and triploidy, age-independent) is approximately twice the risk of Down syndrome [8]. Advanced maternal age is also associated with subfertility, because chromosomally abnormal embryos have a lower implantation rate, and with dizygotic twinning [8].

8.4. When to refer to the genetics clinic

The Oxford Desk Reference considers that recurrent losses with normal parental chromosomes are not in themselves an indication for referral to a genetics clinic, and that couples with a significant history, especially with cytogenetic anomalies in the tissue, may be referred. Assessment includes a three-generation pedigree focused on miscarriages, stillbirths, neonatal deaths and unexplained disability or congenital anomaly; physical examination is generally not warranted. Without a parental rearrangement, couples are best followed in a reproductive medicine clinic [3]. Referral to a genetics clinic is justified by: a structural imbalance in the tissue (for parental karyotyping and counselling on translocations); repeated moles or a biparental diploid mole (testing of NLRP7 and KHDC3L) [10]; recurrent loss of male fetuses in a family with an X-linked dominant disorder [3]; maternal consanguinity with familial mole [72]; and monogenic variants identified by exome sequencing of the tissue. The case in section 10 ended with a recommendation for referral to a genetics clinic [84].

8.5. Robertsonian translocations and other parental causes

Carriers of Robertsonian translocations (about 1/1000; rob(13q14q) about 1/1300) produce disomic or nullisomic gametes through adjacent segregation; monosomic conceptions miscarry or do not even reach a confirmed pregnancy. In der(13;14) carriers, the miscarriage rate was 28% in female carriers and 20% in partners of male carriers; in oocytes, 33% of those from rob(13q14q) carriers and 42% of those from rob(14q21q) carriers were unbalanced [68]. Faced with recurrent miscarriages in a Robertsonian carrier without another cause, the Oxford Desk Reference recommends reassuring the couple that most eventually have a normal pregnancy, confirming the anomaly in the tissue when possible and considering preimplantation genetic testing after three or more miscarriages (non-homologous translocation) or in oligospermia of the male carrier; in maternally transmitted rob(14q21q), the 10% to 15% risk of Down syndrome justifies discussing invasive prenatal diagnosis [68].

8.6. Recurrent mole and maternal-effect genes

In women with biallelic variants in NLRP7 or KHDC3L, there is no treatment that corrects the defect, which lies in the oocytes; oocyte donation is the documented route to a normal pregnancy (three additional live births in two women; one term birth in another report; in a 17-year prospective cohort of 23 women, 3 of 4 women having IVF with donated oocytes had a live birth), and preimplantation genetic testing of the woman's own oocytes does not help; after a birth from a donated oocyte, a spontaneous conception again produced a complete mole [10, 11]. The reports compiled in OMIM show the limits of this route: in an Italian family, a pregnancy attempted through oocyte donation ended in a persistent mole, treated with methotrexate, which genotyping showed to originate from one of the patient's own oocytes; in an Iranian woman homozygous for the M1V initiation variant of KHDC3L, embryos from her oocytes transferred to a gestational surrogate gave rise to a partial mole, which places the defect in the oocyte and not in the uterus, and transfer of two blastocysts from donated oocytes did not result in an ongoing pregnancy; in a Chinese woman homozygous for a 1-base-pair deletion in KHDC3L, all embryos from two intracytoplasmic sperm injection (ICSI) cycles arrested at the morula stage [12, 13]. Women with two or more biparental diploid complete moles may be counselled as confirmed carriers even without an identified variant [11]. An androgenetic recurrent mole does not rule out a maternal cause, because the forms due to MEI1, C11orf80/TOP6BL, HFM1 and KASH5 produce monospermic androgenetic complete moles; genotyping of the tissue is therefore not sufficient to decide whom to test, and these genes belong on the extended panel for women with recurrent moles without NLRP7 or KHDC3L variants. In the families described with MEI1 and C11orf80/TOP6BL, no affected woman had a live birth, and the progression of both moles of a patient with KASH5 to gestational trophoblastic neoplasia reinforces hCG follow-up after each mole [16–19]. In multilocus imprinting disturbances due to maternal-effect genes, there is no reliable prenatal test for multilocus methylation changes, preimplantation genetic testing is not possible and prenatal sequencing for the maternal variant is not indicated, because the offspring are heterozygous carriers [33].

8.7. Prenatal and preimplantation diagnosis

After a sporadic aneuploid loss, prenatal diagnosis in a subsequent pregnancy has no specific indication and follows the rules for maternal age and screening [9]. After a triploidy, prenatal diagnosis is discretionary and not specifically indicated, because most triploid conceptions fail spontaneously [72]. cfDNA screening, CVS and amniocentesis have the limitations and risks described in section 5.11. Preimplantation genetic testing for aneuploidy (PGT-A) and for structural rearrangements (PGT-SR) belongs to the context of recurrent loss and infertility.

8.8. Relatives and minors

A de novo aneuploidy in the tissue has no implications for relatives and does not justify cascade testing. Only inherited structural rearrangements and variants in maternal-effect genes or fetal monogenic variants justify testing relatives. There is no indication to test minors in the context of a sporadic loss.

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

The frequency of pregnancy loss depends on what is counted. Studies with daily hCG measurement measure loss from implantation (31% in the United States) [34]; national registries measure losses with hospital contact (13.5% of intended pregnancies in Denmark; lowest risk of 10% at 25–29 years in Norway) [85, 86]; guidelines cite 10% of clinically recognised pregnancies [4]. The proportion of anembryonic pregnancies among losses is known only from hospital cohorts: in IVF in China, 24.4% of early losses after transfer of top-quality cleavage-stage embryos and 45.9% after extended culture to blastocyst of lower-quality embryos [63]; 17.2% (266/1551) of karyotyped miscarriages in the Tomsk series [5]. None of these proportions is a population prevalence, and the sources consulted do not provide a validated population estimate.

9.2. Data by region

United States. The Wilcox cohort (221 women) is the reference for preclinical loss [34]. North American cytogenetic series include 2301 products of conception in New York (1990–2002), with an increase in the anomaly rate from 42.8% to 65.8% after technical improvements [56]; 2392 SNP-array samples from a commercial laboratory, with maternal contamination in 22.0% [51]; 8118 CMA samples, 83% from recurrent losses or miscarriages [35]; and 272 curettages at an infertility clinic in Stanford (1999–2006), with 65% anomalies [50]. Warburton and colleagues included women from New York and Honolulu [9].

Europe. In Denmark, the 1978–1992 registry measured risk by age [85], the triploidy registry identified 183 triploid pregnancies among 1.5 million clinically confirmed pregnancies, mostly associated with molar disease [72], and the Copenhagen COPL cohort (1463 women, 2020–2022) studied cfDNA after loss [99]. In Norway, the 2009–2013 registry quantified the effect of age and reproductive history [86]. In France, Boué and colleagues studied 1500 miscarriages between 1966 and 1972 and found more anomalies after ovulation induction and after paternal occupational exposure to radiation, with no effect of oral contraceptives [46]. In Italy, Minelli and colleagues studied 52 anembryonic pregnancies [36] and Savarese and colleagues 299 cfDNA samples (2022–2025) [67]. In the United Kingdom, the MIST and MifeMiso trials and the Abdallah and Preisler cohorts defined the criteria and management [87, 88, 94, 130]. In Ukraine, 1000 first-trimester miscarriages had 50.1% anomalies, more in women over 40 than in those under 35 [58]. In Russia (Tomsk), the series of 1551 miscarriages covers 1990–2022 [5]. In Slovakia, the gestational trophoblastic disease centre described the case in section 10 [84]. In Poland, a preprint describes the increasing uptake of tissue testing in a tertiary centre [89].

Other regions. Chinese series are the largest of recent years: 1102 losses by CMA [62], 1765 IVF pregnancies [63], 1585 tissues in Urumqi [60], 21,311 fetuses in Zhengzhou [74] and 564 miscarriages by SNP-array [59]. There are series from Thailand (BACs-on-Beads in AP, 2010–2022) [37], Vietnam (636 losses in 18 centres, 2022–2024) [80], India (172 products of conception) [79], Turkey (flow cytometry) [64], Colombia (11 miscarriages) [65] and Israel (recurrent loss) [102, 135]. Hassold and colleagues found no difference in the proportion of anomalies between five racial groups and attributed the differences between studies to sample selection [47].

Founder populations, Portugal and Brazil. Sporadic loss due to aneuploidy has no known variation by ancestry, and the sources consulted do not describe founder effects. NLRP7 variants associated with recurrent mole were described in an Indian series (20 of 23 women with recurrent moles and no live birth had biallelic variants) [10]. Recurrent mole has founder variants: in a review of 200 probands with NLRP7 variants, L750V (historical numbering, = NM_001127255.2:c.2248C>G p.(Leu750Val)) accounted for 79% of alleles in Mexican cases and a 54-base-pair insertion (Arg937_Leu938ins54) was observed in 10 unrelated Mexican patients; at codon 693, R693W (= NM_001127255.2:c.2077C>T p.(Arg693Trp)) occurs in Turkish patients and patients of European ancestry from several countries, R693P (= NM_001127255.2:c.2078G>C p.(Arg693Pro)) is the main variant in Indo-Pakistani patients (39% of alleles) and R693Q (= NM_001127255.2:c.2078G>A p.(Arg693Gln)) has been described only in Chinese patients (11%); a frameshift variant, Glu710Aspfs, is the most frequent in Egyptian patients (32% of alleles). R693P and N913S (= NM_001127255.2:c.2738A>G p.(Asn913Ser)) have a founder effect demonstrated by haplotypes in India, and the KHDC3L deletion NM_001017361.3:c.322_325del p.(Asp108IlefsTer30) shares a haplotype in families of Indian, Turkish and Tunisian origin. The incidence of hydatidiform mole in general varies between ethnic groups, from about 1 in 250 pregnancies in East Asia to about 1 in 1500 in the United States, according to a 1999 summary [12–14]. The cytogenetic series and trials consulted do not include data from Portugal or Brazil; their absence from these sources does not demonstrate that no published data exist.

9.3. Special populations

Advanced maternal age. This is the main risk factor for aneuploid loss and for loss overall (sections 3.2 and 8.3) [8, 85]. In the Urumqi cohort, the relationship between maternal age and risk of an anomaly was U-shaped, with a minimum at 28–29 years and a rise from 30; the authors propose 30 years as a threshold, which is an opinion [60]. 45,X conceptions are associated with younger mothers [8, 74].

Assisted reproduction. In IVF, extended culture to blastocyst of lower-quality cleavage-stage embryos almost doubled the proportion of AP among losses (45.9% versus 24.4%; p = 0.037), and blastocyst transfer and advanced maternal age were risk factors for AP [63]. In the Ukrainian series, there was no difference in the frequency of anomalies between conceptions by intracytoplasmic sperm injection (ICSI) and spontaneous conceptions [58]. Chromosomally abnormal embryos have a lower implantation rate [8].

Multiple pregnancy. Spontaneous resorption of a second sac in the first trimester is frequent and may confound cfDNA screening [92].

Adolescents. FIGO provides for cervical preparation before aspiration at 17 years or under [105]; cytogenetic series do not address this group separately.

9.4. Reference networks and patient organisations

ERN ITHACA (European Network for Rare Malformation Syndromes, according to the title of the website https://ern-ithaca.eu/) is the relevant European network for chromosomal anomalies and malformation syndromes; there is no European Reference Network for sporadic pregnancy loss [44]. In the United Kingdom, Miscarriage UK (working name of The Miscarriage Association, a charity registered in England and Wales, 1076829, and in Scotland, SC039790) provides a helpline, counselling, personal stories and leaflets for professionals (https://www.miscarriageuk.org/) [3, 136]; Unique (Rare Chromosome Disorder Support Group, https://www.rarechromo.org) supports families with rare chromosomal anomalies [72]; ARC (Antenatal Results and Choices, https://www.arc-uk.org) supports decisions after prenatal diagnosis [76]. In the United States, Share Pregnancy & Infant Loss Support (https://nationalshare.org/) supports families after pregnancy loss [137]. ESHRE publishes a patient guide on recurrent pregnancy loss [138]. The sources consulted do not identify Portuguese or Brazilian patient organisations dedicated to pregnancy loss.

10. Illustrative Clinical Case

Gergely and colleagues, from the Slovak Gestational Trophoblastic Disease Centre, published in 2023 the case of a 45-year-old woman with an anembryonic pregnancy mimicking a partial mole [84]. Transvaginal ultrasound, at 7 weeks by biometry (10 weeks by last menstrual period), showed an irregular amniotic cavity without an embryonic structure and a «molar placenta» with multiple small cystic spaces, with a «Swiss cheese» appearance (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10669944/figure/f1-pr72_s309/). Serum hCG was 50,951 IU/L. The woman had had a caesarean section four years earlier, with the birth of a healthy boy, and a complete early miscarriage at 8 weeks nine months earlier, whose expelled tissue had been sent for histology.

Given the suspicion of a partial mole, uterine evacuation was performed. The villi were separated into saline for DNA extraction and the remaining tissue fixed in formalin. Histology showed regressive hydropic villous remnants; immunohistochemistry showed positive p57 in the cytotrophoblast (up to 70%), which excluded a complete mole, weak placental alkaline phosphatase (PLAP) and a Ki67 index below 25% (figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10669944/figure/f2-pr72_s309/). QF-PCR genotyping of STR markers (GenePrint 10) showed a biparental diploid genome, with one maternal and one paternal contribution, which excluded a triploid partial mole. Aneuploidy QF-PCR (Devyser Extend v2, chromosomes 13, 15, 16, 18, 21, 22, X and Y) showed an XX gonosomal complement with trisomy 16 and trisomy 22, both of maternal origin; the formula 48,XX,+16,+22 is an equivalence and was not used by the authors. The karyotypes of the woman and her 48-year-old partner were normal. Retrospective analysis of the paraffin blocks from the first loss, after microdissection, showed an XY conceptus with trisomy 18 of maternal origin (figure 3 of the article, electropherograms: https://pmc.ncbi.nlm.nih.gov/articles/PMC10669944/figure/f3-pr72_s309/). The figures were identified from the captions and the page links; the images were not viewed.

The authors attributed both losses to age-related maternal meiotic errors, with no structural parental cause, concluded that aneuploidies may mimic a partial mole on ultrasound and clinically and that QF-PCR avoids culture failure and maternal contamination and works on paraffin-embedded tissue, and recommended referral to a genetics clinic; post-molar hCG follow-up applies only to a proven mole [84]. The management in the report is consistent with the guidelines: evacuation when a mole is suspected, genotyping to clarify the diagnosis and no post-molar follow-up without a confirmed mole [72]. The case illustrates double trisomy, which accounted for 57 of the 1099 abnormal karyotypes in the New York series and predominates in older women [56], and the value of studying paraffin blocks to reconstruct retrospectively the cause of a previous loss.

11. Prognosis and Long-Term Follow-up

11.1. Immediate prognosis

Uterine evacuation is complete in most women with any of the three approaches. Expectant management achieves complete expulsion in about 80% with up to 8 weeks of waiting, with lower effectiveness in anembryonic pregnancy than in incomplete loss [4]; the regimen of mifepristone followed by misoprostol achieved complete expulsion with one dose in 83.8% in PreFaiR [129]; misoprostol alone achieved 71% by day 3 and 84% after a second dose, with 81% success specifically in anembryonic pregnancy in the NICHD trial [4]; and aspiration approaches 99% [4]. Haemorrhage requiring admission or transfusion (0.5% to 1%) and infection (1% to 2%) are rare [4].

11.2. Reproductive prognosis

The reproductive prognosis after a sporadic loss is favourable. After an aneuploid miscarriage, the risk of trisomy in the next miscarriage does not increase [9], and in recurrent loss the subsequent live birth rate was 68% after an aneuploid miscarriage versus 41% after a euploid miscarriage [135]. The risk of a further loss increases with the number of previous losses (OR 1.54 after one, 2.21 after two and 3.97 after three) and with maternal age (lowest risk of 10% at 25–29 years and 53% at 45 years or over, in Norway) [86]. The slightly higher risk of miscarriage after preterm birth (OR 1.22), stillbirth (1.30), caesarean section (1.16) and gestational diabetes (1.19) points to maternal factors common to several outcomes [86]. Curettage is associated with preterm birth in a future pregnancy (OR 1.29 before 37 weeks) and with intrauterine adhesions (19.1% at hysteroscopy up to 12 months), especially with repeated curettages [118, 119].

After a mole, persistent trophoblastic disease occurs, in the United Kingdom, in 15% of complete moles and in 0.5% to 1% of partial moles, and cure with chemotherapy exceeds 98% [72]. In women with biallelic NLRP7 variants, trophoblastic neoplasia occurred in 50% in an Indian series, two to three times the rate after sporadic moles [10].

11.3. Surveillance table

The interval for hCG surveillance after a mole is not stated in the sources consulted; the Oxford Desk Reference refers to the British follow-up registry (http://www.hmole-chorio.org.uk) [72], and GeneGuidance cites the 2015 Danish and the 2016 German-Austrian-Swiss guidelines [10].

11.4. Psychological follow-up and information

NICE recommends offering a follow-up appointment with the professional of the woman's choice, information on physical and emotional recovery, conceiving again and future fertility, and contacts for support organisations [38]. WHO considers a routine follow-up visit after uncomplicated treatment unnecessary, provided the woman knows the warning signs and knows that she can seek additional services [43]. The two positions are not incompatible: the first concerns support, the second the medical need for reassessment.

12. Summary and Final Considerations

Anembryonic pregnancy is an intrauterine gestational sac without an embryo, diagnosed by transvaginal ultrasound with criteria designed to avoid false positives: MSD of 25 mm or more without an embryo, or absence of an embryo on serial scans at defined intervals. The 2024 SRU lexicon replaced blighted ovum with «anembryonic pregnancy» and «pregnancy failure» with «early pregnancy loss». Before the diagnosis is concluded, a sac of less than 25 mm requires a repeat scan, and an isolated intrauterine sac does not exclude ectopic pregnancy.

About half of early losses result from a chromosomal anomaly of the conceptus, almost always sporadic. In anembryonic pregnancy, autosomal trisomies (mainly 16, 22 and 15) and tetraploidy predominate; monosomy X and triploidy, which allow initial embryonic development, are less frequent than in miscarriages with an embryo. The overall frequency of anomalies in anembryonic pregnancy is similar to that of miscarriage with an embryo in some karyotype series and lower in others, especially those that use microarray and study the empty sac; in the compilation of 12 studies it was 44.4% versus 59.3%. Technique, selection and maternal contamination explain part of the divergence, and the causes of euploid losses remain unclear.

Genetic analysis of the products of conception explains the loss and guides counselling, but guidelines diverge on when to perform it: not routinely after one loss (ACOG, ESHRE), from the second (ASRM 2026) or from the third (RCOG). When performed, SNP microarray, or QF-PCR followed by microarray, with control for maternal contamination, is preferable to karyotyping, which fails in 10% to 40% of samples; triploidy requires a technique with allelic information. Without tissue, maternal cfDNA collected before expulsion or within the following 12 hours offers an alternative with a pooled sensitivity of 78% and specificity of 91%, in which a negative result does not exclude aneuploidy.

Management does not depend on the chromosomal cause. Expectant management, medical treatment with mifepristone 200 mg followed, 24 to 48 hours later, by misoprostol 800 µg, and uterine aspiration are valid options, chosen with the woman; mifepristone increases complete expulsion and reduces surgery. These drugs are used outside their labelled indications in Portugal, the United States and Brazil, where mifepristone is not registered. Anti-D immunoglobulin before 12 weeks is no longer recommended by NICE, WHO and CNGOF, and since 2024 ACOG has suggested forgoing it routinely, but SMFM maintains that it should be offered. After a sporadic aneuploid loss, the risk of recurrence is that of maternal age and the reproductive prognosis is favourable; the exceptions (inherited structural imbalance, repeated moles, maternal-effect genes) justify referral to a genetics clinic.

13. References

1. Rodgers SK, Horrow MM, Doubilet PM, Frates MC, Kennedy A, Andreotti R, et al. A Lexicon for First-Trimester US: Society of Radiologists in Ultrasound Consensus Conference Recommendations. Radiology. 2024;312(2):e240122. doi:10.1148/radiol.240122 PMID: 39189906; PMC11366677
2. Kolte AM, Bernardi LA, Christiansen OB, Quenby S, Farquharson RG, Goddijn M, et al. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod. 2015;30(3):495-8. doi:10.1093/humrep/deu299 PMID: 25376455
3. Miscarriage and recurrent miscarriage. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 760–761.
4. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin No. 200: Early pregnancy loss. Obstet Gynecol. 2018;132(5):e197-e207. doi:10.1097/AOG.0000000000002899. PMID: 30157093. Reaffirmed 2025. Available from: https://journals.lww.com/greenjournal/fulltext/10.1097/aog.0000000000002899
5. Nikitina TV, Sazhenova EA, Tolmacheva EN, Sukhanova NN, Vasilyev SA, Lebedev IN. Comparative cytogenetics of anembryonic pregnancies and missed abortions in human. Vavilovskii Zhurnal Genet Selektsii. 2023;27(1):28-35. doi:10.18699/VJGB-23-05 PMID: 36923481; PMC10009480
6. Ha S, Liu W, Yuan P, Yuan S, Cao C, Meng A, et al. Maternal genetic variants associated with aneuploid conception: a narrative review. Hum Reprod Update. 2026;32(5):587-612. doi:10.1093/humupd/dmag012 PMID: 42124334
7. McCoy RC, Demko Z, Ryan A, Banjevic M, Hill M, Sigurjonsson S, et al. Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos. Science. 2015;348(6231):235-8. doi:10.1126/science.aaa3337 PMID: 25859044; PMC5519344
8. Maternal age. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 754–755.
9. Warburton D, Kline J, Stein Z, Hutzler M, Chin A, Hassold T. Does the karyotype of a spontaneous abortion predict the karyotype of a subsequent abortion? Evidence from 273 women with two karyotyped spontaneous abortions. Am J Hum Genet. 1987;41(3):465-83. PMID: 3631080; PMC1684190
10. GeneGuidance. NLRP7 — clinical curation (version of 2026-09-26).
11. GeneGuidance. KHDC3L — clinical curation and condition Hydatidiform mole, recurrent, 2 (version of 2026-09-26).
12. OMIM® Online Mendelian Inheritance in Man. #231090 HYDATIDIFORM MOLE, RECURRENT, 1; HYDM1. Johns Hopkins University; last edited 23/09/2026. https://omim.org/entry/231090. Accessed 28 October 2026.
13. OMIM® Online Mendelian Inheritance in Man. #614293 HYDATIDIFORM MOLE, RECURRENT, 2; HYDM2. Johns Hopkins University; last edited 12/10/2026. https://omim.org/entry/614293. Accessed 28 October 2026.
14. OMIM® Online Mendelian Inheritance in Man. *609661 NLR FAMILY, PYRIN DOMAIN-CONTAINING 7; NLRP7. Johns Hopkins University; last edited 30/01/2026. https://omim.org/entry/609661. Accessed 28 October 2026.
15. OMIM® Online Mendelian Inheritance in Man. *611687 KHDC3-LIKE PROTEIN, SUBCORTICAL MATERNAL COMPLEX MEMBER; KHDC3L. Johns Hopkins University; last edited 12/10/2026. https://omim.org/entry/611687. Accessed 28 October 2026.
16. OMIM® Online Mendelian Inheritance in Man. #618431 HYDATIDIFORM MOLE, RECURRENT, 3; HYDM3. Johns Hopkins University; last edited 15/06/2026. https://omim.org/entry/618431. Accessed 28 October 2026.
17. OMIM® Online Mendelian Inheritance in Man. #618432 HYDATIDIFORM MOLE, RECURRENT, 4; HYDM4. Johns Hopkins University; last edited 27/12/2021. https://omim.org/entry/618432. Accessed 28 October 2026.
18. OMIM® Online Mendelian Inheritance in Man. #621720 HYDATIDIFORM MOLE, RECURRENT, 5; HYDM5. Johns Hopkins University; last edited 23/09/2026. https://omim.org/entry/621720. Accessed 28 October 2026.
19. OMIM® Online Mendelian Inheritance in Man. #621721 HYDATIDIFORM MOLE, RECURRENT, 6; HYDM6. Johns Hopkins University; last edited 23/09/2026. https://omim.org/entry/621721. Accessed 28 October 2026.
20. OMIM® Online Mendelian Inheritance in Man. #621471 OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 25; OZEMA25. Johns Hopkins University; last edited 30/01/2026. https://omim.org/entry/621471. Accessed 28 October 2026.
21. Orphanet. Trisomy 13 syndrome. ORPHA:3378. https://www.orpha.net/en/disease/detail/3378
22. Orphanet. Trisomy 18 syndrome. ORPHA:3380. https://www.orpha.net/en/disease/detail/3380
23. Orphanet. Down syndrome. ORPHA:870. https://www.orpha.net/en/disease/detail/870
24. Orphanet. Mosaic trisomy 16 syndrome. ORPHA:1708. https://www.orpha.net/en/disease/detail/1708
25. Orphanet. Mosaic trisomy 22 syndrome. ORPHA:96068. https://www.orpha.net/en/disease/detail/96068
26. Orphanet. Mosaic trisomy 15 syndrome. ORPHA:1706. https://www.orpha.net/en/disease/detail/1706
27. Orphanet. Triploidy syndrome. ORPHA:3376. https://www.orpha.net/en/disease/detail/3376
28. Orphanet. Tetraploidy syndrome. ORPHA:3305. https://www.orpha.net/en/disease/detail/3305
29. Orphanet. Turner syndrome. ORPHA:881. https://www.orpha.net/en/disease/detail/881
30. Orphanet. Hydatidiform mole. ORPHA:99927. https://www.orpha.net/en/disease/detail/99927
31. Orphanet. Complete hydatidiform mole. ORPHA:254688. https://www.orpha.net/en/disease/detail/254688
32. Orphanet. Partial hydatidiform mole. ORPHA:254693. https://www.orpha.net/en/disease/detail/254693
33. Tümer Z, Eggermann T, Maas S, Bliek J, Mackay D. Maternal Effect Gene-Related Multilocus Imprinting Disturbances. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2025 May 15 [revised 2025 Aug 28]. NBK614473. https://www.ncbi.nlm.nih.gov/books/NBK614473/
34. Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319(4):189-94. doi:10.1056/NEJM198807283190401 PMID: 3393170
35. Sahoo T, Dzidic N, Strecker MN, Commander S, Travis MK, Doherty C, et al. Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges. Genet Med. 2017;19(1):83-89. doi:10.1038/gim.2016.69 PMID: 27337029
36. Minelli E, Buchi C, Granata P, Meroni E, Righi R, Portentoso P, et al. Cytogenetic findings in echographically defined blighted ovum abortions. Ann Genet. 1993;36(2):107-10. PMID: 8215215
37. Onsod P, Jaranasaksakul W, Chareonsirisuthigul T, Parinayok R, Rerkamnuaychoke B, Areesirisuk P. Chromosomal abnormalities study for anembryonic pregnancy by BACs-on-Beads technique. Eur J Obstet Gynecol Reprod Biol. 2024;298:31-34. doi:10.1016/j.ejogrb.2024.04.041 PMID: 38705011
38. National Institute for Health and Care Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. NICE guideline NG126. London: NICE; 17 April 2019, last updated 17 June 2026. Available from: https://www.nice.org.uk/guidance/ng126
39. ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. Recurrent pregnancy loss: guideline of the European Society of Human Reproduction and Embryology. Update 2022 (final version January 2023). Strombeek-Bever: ESHRE; 2023. Available from: https://www.eshre.eu/-/media/sitecore-files/Guidelines/Recurrent-pregnancy-loss/2022/ESHRE-RPL-Guideline-_-Update-2022_-Final-Version-January-2023_v2.pdf
40. Practice Committee of the American Society for Reproductive Medicine. Recurrent pregnancy loss: a committee opinion. Fertil Steril. 2026;125(6):1023-1041. doi:10.1016/j.fertnstert.2026.03.001. PMID: 42062119.
41. Regan L, Rai R, Saravelos S, Li TC. Recurrent Miscarriage: Green-top Guideline No. 17. BJOG. 2023;130(12):e9-e39. doi:10.1111/1471-0528.17515. PMID: 37334488.
42. Pauta M, Martinez-Portilla RJ, Jara-Ettinger AC, Ardiles-Ruesjas V, Borrell A. Genome-Wide Cell-Free DNA Analysis for Aneuploidy Detection in Miscarriages: Test Performance Meta-Analysis. Prenat Diagn. 2025;45(8):957-967. doi:10.1002/pd.6824 PMID: 40423663; PMC12254433
43. World Health Organization. Abortion care guideline. 2nd ed. Geneva: WHO; 2024. ISBN 978-92-4-010420-4. Licence: CC BY-NC-SA 3.0 IGO. Available from: https://www.ncbi.nlm.nih.gov/books/NBK617985/
44. European Reference Network ITHACA — European Network for Rare Malformation Syndromes [Internet]. Available from: https://ern-ithaca.eu/
45. Donald I, Morley P, Barnett E. The diagnosis of blighted ovum by sonar. J Obstet Gynaecol Br Commonw. 1972;79(4):304-10. doi:10.1111/j.1471-0528.1972.tb15801.x PMID: 5025136
46. Boué J, Bou A, Lazar P. Retrospective and prospective epidemiological studies of 1500 karyotyped spontaneous human abortions. Teratology. 1975;12(1):11-26. doi:10.1002/tera.1420120103 PMID: 1162621
47. Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B, Matsuura J, et al. A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet. 1980;44(2):151-78. doi:10.1111/j.1469-1809.1980.tb00955.x PMID: 7316468
48. Henderson DJ, Bennett PR, Rodeck CH, Gau GS, Blunt S, Moore GE. Trophoblast from anembryonic pregnancy has both a maternal and a paternal contribution to its genome. Am J Obstet Gynecol. 1991;165(1):98-102. doi:10.1016/0002-9378(91)90233-h PMID: 1853926
49. Witter FR, Blakemore KJ, Callan NA. Transition from normal early pregnancy to blighted ovum. Int J Gynaecol Obstet. 1991;36(1):63-5. doi:10.1016/0020-7292(91)90181-4 PMID: 1683306
50. Lathi RB, Mark SD, Westphal LM, Milki AA. Cytogenetic testing of anembryonic pregnancies compared to embryonic missed abortions. J Assist Reprod Genet. 2007;24(11):521-4. doi:10.1007/s10815-007-9166-1 PMID: 17899357; PMC3455028
51. Levy B, Sigurjonsson S, Pettersen B, Maisenbacher MK, Hall MP, Demko Z, et al. Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis. Obstet Gynecol. 2014;124(2 Pt 1):202-209. doi:10.1097/AOG.0000000000000325 PMID: 25004334
52. Nikitina TV, Fonova EA, Lebedev IN. Genomics of pregnancy loss. J Assist Reprod Genet. 2026;43(1):3-18. doi:10.1007/s10815-025-03726-9 PMID: 41134463; PMC12831732
53. Cell division—mitosis, meiosis, and non-disjunction. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 646–651.
54. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet. 2001;2(4):280-91. doi:10.1038/35066065 PMID: 11283700
55. Paternal age. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 772–773.
56. Menasha J, Levy B, Hirschhorn K, Kardon NB. Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet Med. 2005;7(4):251-63. doi:10.1097/01.gim.0000160075.96707.04 PMID: 15834243
57. Wou K, Hyun Y, Chitayat D, Vlasschaert M, Chong K, Wasim S, et al. Analysis of tissue from products of conception and perinatal losses using QF-PCR and microarray: A three-year retrospective study resulting in an efficient protocol. Eur J Med Genet. 2016;59(8):417-24. doi:10.1016/j.ejmg.2016.05.011 PMID: 27233578
58. Pylyp LY, Spynenko LO, Verhoglyad NV, Mishenko AO, Mykytenko DO, Zukin VD. Chromosomal abnormalities in products of conception of first-trimester miscarriages detected by conventional cytogenetic analysis: a review of 1000 cases. J Assist Reprod Genet. 2018;35(2):265-271. doi:10.1007/s10815-017-1069-1 PMID: 29086320; PMC5845039
59. Zhao W, Wang H, Liang B, Huang H, Lin N, Xu L. Identification of chromosomal abnormalities in miscarriages using single-nucleotide polymorphism arrays. Arch Gynecol Obstet. 2026;313(1):253. doi:10.1007/s00404-026-08337-y PMID: 42271033; PMC13478020
60. Wang L, Liu P, Huang W, Li M, Yin J, Xue S. The genetic etiology of spontaneous abortion: insights from chromosomal microarray analysis and whole-exome sequencing. Sci Rep. 2026;16(1):25974. doi:10.1038/s41598-026-53777-w PMID: 42260280; PMC13486647
61. Stephenson MD, Awartani KA, Robinson WP. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum Reprod. 2002;17(2):446-51. doi:10.1093/humrep/17.2.446 PMID: 11821293
62. Gu C, Li K, Li R, Li L, Li X, Dai X, et al. Chromosomal Aneuploidy Associated With Clinical Characteristics of Pregnancy Loss. Front Genet. 2021;12:667697. doi:10.3389/fgene.2021.667697 PMID: 33936179; PMC8083898
63. Zhu Y, Zhou Y, Liu S, Guo F, Wu B, Xu X, et al. Blastocyst culture of non-top-quality cleavage embryos may increase the risk of anembryonic pregnancy following in vitro fertilization: a retrospective cohort study. Ann Transl Med. 2022;10(24):1364. doi:10.21037/atm-22-5809 PMID: 36660687; PMC9843398
64. Ozeren M, Aydemir V, Tekelioglu Y, Topçuoglu K, Bozkaya H. Ploidy analysis and S-phase fraction determination by flow cytometry in anembryonic pregnancy and spontaneous abortions. Gynecol Obstet Invest. 1999;48(2):104-7. doi:10.1159/000010149 PMID: 10461000
65. Agudelo B, Muneton CM, Vasquez G, Ramirez JL. Correlation between serum levels of 17 beta-estradiol, progesterone and beta-human chorionic gonadotropin and the karyotype of first trimester anembryonic and embryonic pregnancies. Early Pregnancy (Cherry Hill). 2001;5(3):176-90. PMID: 11753531
66. Alberry M, Maddocks D, Jones M, Abdel Hadi M, Abdel-Fattah S, Avent N, et al. Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast. Prenat Diagn. 2007;27(5):415-8. doi:10.1002/pd.1700 PMID: 17286310
67. Savarese G, Guida M, Ianniello M, Ruggiero R, Ottaiano A, Marcella S, et al. Noninvasive Cell-Free DNA-Based Approach for the Diagnosis of Aneuploidies in Spontaneous Abortion. Fetal Diagn Ther. 2026;:1-6. doi:10.1159/000551626 PMID: 42435360
68. Robertsonian translocations. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 684–687.
69. Down's syndrome (trisomy 21). In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 666–669.
70. Edwards' syndrome (trisomy 18). In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 670–671.
71. Patau syndrome (trisomy 13). In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 678–679.
72. Triploidy (69,XXX, 69,XXY, or 69,XYY). In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 694–695.
73. Turner syndrome, 45,X, and variants. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 696–699.
74. Zhu Y, Liu Y, Ren C, Liu J, Yang Q, Li N, et al. New insight about early miscarriage: a prenatal data-based study. J Transl Med. 2026;24(1):686. doi:10.1186/s12967-026-08096-z PMID: 41943072; PMC13188703
75. Autosomal reciprocal translocations—background. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 636–639.
76. Chromosomal mosaicism—prenatal. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 654–659.
77. Invasive techniques and genetic tests in prenatal diagnosis. In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 744–747.
78. Bozhinovski G, Noveski P, Terzikj M, Kubelka-Sabit K, Plaseska-Karanfilska D. Monogenic Findings in Early Pregnancy Loss: Whole-Exome Sequencing Study of Euploid Products of Conception. Balkan J Med Genet. 2025;28(2):5-20. doi:10.2478/bjmg-2025-00028 PMID: 42147992; PMC13175650
79. Yadam Reddy KDD, Kumaraswamy S, Palanikumar P, Hussain T, Naushad SM. Clinical utility of chromosomal microarray and whole exome sequencing in evaluating genetic causes for pregnancy loss using products of conception specimens. J Perinat Med. 2026;54(3):507-514. doi:10.1515/jpm-2025-0240 PMID: 41331780
80. Thai MD, Nguyen KV, Lu YT, Le Nguyen TH, Phan MN, Van Pham H, et al. Genetic Etiology of Miscarriage in a Vietnamese Cohort Using CNV-Seq and Exome Sequencing. Prenat Diagn. 2026;46(11):1760-1770. doi:10.1002/pd.70215 PMID: 42438204
81. Yatsenko SA, Nagasuri A, Soman V, Garakani A, Aminbeidokhti M, Chandran U, et al. The Human Intolerome: A curated database to prioritize genomic variants in stillbirth, pregnancy loss, and neonatal death. Genet Med. 2026;28(6):102546. doi:10.1016/j.gim.2026.102546 PMID: 41793222; PMC13004823
82. McCoy RC, Newnham LJ, Ottolini CS, Hoffmann ER, Chatzimeletiou K, Cornejo OE, et al. Tripolar chromosome segregation drives the association between maternal genotype at variants spanning PLK4 and aneuploidy in human preimplantation embryos. Hum Mol Genet. 2018;27(14):2573-2585. doi:10.1093/hmg/ddy147 PMID: 29688390; PMC6030883
83. Zhang Q, Wu X, Liu X, Wei J, Wang L, Cao J, et al. Dysregulation of SCARB1 Alternative Splicing Disturbs Amino Acid Metabolism in Anembryonic Pregnancy. Reprod Sci. 2026;:. doi:10.1007/s43032-026-02179-4 PMID: 42778874
84. Gergely L, Korbeľ M, Adamec A, Repiská V, Babál P, Melišová K, et al. Double Trisomy 16 and 22 Clinically Mimic Partial Hydatidiform Mole in a Case of Subsequent Pregnancy Loss. Physiol Res. 2023;72(S3):S309-S313. doi:10.33549/physiolres.935174 PMID: 37888974; PMC10669944
85. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ. 2000;320(7251):1708-12. doi:10.1136/bmj.320.7251.1708 PMID: 10864550; PMC27416
86. Magnus MC, Wilcox AJ, Morken NH, Weinberg CR, Håberg SE. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study. BMJ. 2019;364:l869. doi:10.1136/bmj.l869 PMID: 30894356; PMC6425455
87. Abdallah Y, Daemen A, Guha S, Syed S, Naji O, Pexsters A, et al. Gestational sac and embryonic growth are not useful as criteria to define miscarriage: a multicenter observational study. Ultrasound Obstet Gynecol. 2011;38(5):503-9. doi:10.1002/uog.10075 PMID: 21858883
88. Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial). BMJ. 2006;332(7552):1235-40. doi:10.1136/bmj.38828.593125.55 PMID: 16707509; PMC1471967
89. Klimaszyk K, Ziółkowska K, Kędzia M, et al. Trends in genetic testing of products of conception following pregnancy loss: a four-year retrospective study [preprint]. Research Square. 2026 Sep 10. doi:10.21203/rs.3.rs-10864633/v1
90. Bunjamin IA, Gianina K, Nisa AS, Bhanuwati QR, Juslin NP, Aziz MA, et al. Diagnostic Pitfall: Intrauterine Pseudogestational Sac Mimicking an Anembryonic Pregnancy in Tubal Ectopic Pregnancy A Case Report. Int J Womens Health. 2026;18:582019. doi:10.2147/IJWH.S582019 PMID: 41821756; PMC12977989
91. Lin S, An D, Xu Z. Submucosal uterine leiomyoma with complete cystic degeneration mimicking an empty gestational sac: a case report and literature review. Front Med (Lausanne). 2026;13:1858581. doi:10.3389/fmed.2026.1858581 PMID: 42433985; PMC13350315
92. Non-invasive prenatal diagnosis/testing (NIPD/T). In: Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 764–767.
93. Doubilet PM, Benson CB, Bourne T, Blaivas M, Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy, Barnhart KT, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med. 2013;369(15):1443-51. doi:10.1056/NEJMra1302417 PMID: 24106937
94. Preisler J, Kopeika J, Ismail L, Vathanan V, Farren J, Abdallah Y, et al. Defining safe criteria to diagnose miscarriage: prospective observational multicentre study. BMJ. 2015;351:h4579. doi:10.1136/bmj.h4579 PMID: 26400869; PMC4580727
95. Foyouzi N, Cedars MI, Huddleston HG. Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss. Fertil Steril. 2012;98(1):151-5. doi:10.1016/j.fertnstert.2012.04.007 PMID: 22748232
96. Lagerwerf RE, Kox L, Rousian M, De Bakker BS, Dawood Y. Miscarriage Tissue Research: Still in Its Infancy. Life (Basel). 2026;16(1):128. doi:10.3390/life16010128 PMID: 41598283; PMC12842794
97. Zheng J, Zhang Q, Xu L, Zhang VW, Zheng J, Zhang C, et al. Screening of triploid in miscarriage tissues using medium-coverage whole genome sequencing with a three-algorithm integrated approach. J Assist Reprod Genet. 2025;42(9):3133-3142. doi:10.1007/s10815-025-03607-1 PMID: 40750717; PMC12559564
98. Della Valle L, Piergianni M, Khalil A, Rizzo G, Mappa I, Matarrelli B, et al. Accuracy of cell-free fetal DNA in detecting chromosomal anomalies in women experiencing miscarriage: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2025;65(1):13-19. doi:10.1002/uog.29131 PMID: 39644510
99. El Sammaa-Aru YI, Hartwig TS, Bro-Jørgensen MH, Münter EJ, Werge L, Banasik K, et al. How big is the time window for cell-free fetal DNA testing after pregnancy loss and which factors are associated with a successful result?. Hum Reprod. 2026;41(5):712-721. doi:10.1093/humrep/deag034 PMID: 41875045
100. Dugoff L, Mabey B, Bordwell J, Pierson S, Johansen Taber K, Muzzey D. Prenatal Cell-Free DNA Screening With Fetal Fraction Amplification at 6-9 Weeks of Gestation. Obstet Gynecol. 2026;148(2):149-156. doi:10.1097/AOG.0000000000006324 PMID: 42166774; PMC13361953
101. GeneGuidance. Mosaic variegated aneuploidy syndrome — condition (version of 2026-09-26).
102. Carp H, Guetta E, Dorf H, Soriano D, Barkai G, Schiff E. Embryonic karyotype in recurrent miscarriage with parental karyotypic aberrations. Fertil Steril. 2006;85(2):446-50. doi:10.1016/j.fertnstert.2005.07.1305 PMID: 16595225
103. Baghbani F, Mirzaee S, Hassanzadeh-Nazarabadi M. Association of heteromorphism of chromosome 9 and recurrent abortion (ultrasound diagnosed blighted ovum): A case report. Iran J Reprod Med. 2014;12(5):357-60. PMID: 25031581; PMC4094662
104. U.S. Food and Drug Administration. Cytotec (misoprostol) tablets — prescribing information (Pfizer, NDA 019268; approved 1988-12-27), effective 2026-06-04 (DailyMed set ID 4ab12da7-5731-4e06-bf1c-bc3f2e711f12). Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4ab12da7-5731-4e06-bf1c-bc3f2e711f12
105. International Federation of Gynecology and Obstetrics (FIGO). Mifepristone & misoprostol dosing chart: recommended regimens 2023. London: FIGO; 2023. Available from: https://www.figo.org/figo-mifepristone-misoprostol-and-misoprostol-only-dosing-charts-2023 (PDF: https://www.figo.org/sites/default/files/2023-12/FIGO-MifeMiso-Chart-11-2023-FINAL.pdf)
106. Society of Obstetricians and Gynaecologists of Canada. Recommendations for medical management of early pregnancy loss and incomplete early pregnancy loss [chart]. Ottawa: SOGC; n.d. (later than August 2023). Available from: https://www.sogc.org/common/Uploaded%20files/HUB%20Pages/pregnancy-loss/Medical%20Management%20of%20Early%20Pregnancy%20Loss%20and%20Incomplete%20Early%20Pregnancy%20Loss_CHART.pdf
107. Flynn AN, Roe AH, Koelper N, McAllister A, Sammel MD, Schreiber CA. Timing and efficacy of mifepristone pretreatment for medical management of early pregnancy loss. Contraception. 2021;103(6):404-407. doi:10.1016/j.contraception.2021.01.007 PMID: 33476659; PMC10302402
108. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; records NCT07506512, NCT06452719, NCT05198050, NCT05304273, NCT07160855, NCT07109947, NCT07732231, NCT04804332, NCT07646275, NCT05216952, NCT00468299, NCT02573051. Available from: https://clinicaltrials.gov/
109. INFARMED. Mifegyne 200 mg comprimidos (mifepristona; Exelgyn) — Resumo das Características do Medicamento (SmPC), approved 08-07-2024. Infomed. Available from: https://extranet.infarmed.pt/INFOMED-fo/
110. U.S. Food and Drug Administration. Mifepristone tablets, 200 mg (GenBioPro, ANDA 091178) — prescribing information, effective 2026-06-06 (DailyMed set ID b63fad9b-7f12-4400-9019-b0586054e534); Drugs@FDA: Mifeprex NDA 020687 (approved 2000-09-28), ANDA 091178, ANDA 211436, ANDA 216616 (approved 2025-09-30). Available from: https://www.accessdata.fda.gov/scripts/cder/daf/ and https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b63fad9b-7f12-4400-9019-b0586054e534
111. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos — registered medicines (DADOS_ABERTOS_MEDICAMENTOS.csv). Brasília: ANVISA; accessed 2026-10-27. Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
112. INFARMED. Cytotec 0,2 mg comprimidos (misoprostol; Laboratórios Pfizer) — Resumo das Características do Medicamento (SmPC), approved 31-05-2019. Infomed. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=2291&tipo_doc=rcm
113. Infan Indústria Química Farmacêutica Nacional S.A. Prostokos® (misoprostol) comprimidos vaginais 25 µg, 100 µg e 200 µg — package insert for health professionals (registration M.S. 1.1557.0044). Undated version, reproduced at: https://www.saudedireta.com.br/catinc/drugs/bulas/prostokos.pdf (accessed 27/10/2026)
114. Robledo C, Zhang J, Troendle J, Barnhart K, Creinin MD, Westhoff C, et al. Clinical indicators for success of misoprostol treatment after early pregnancy failure. Int J Gynaecol Obstet. 2007;99(1):46-51. doi:10.1016/j.ijgo.2007.04.031 PMID: 17599843; PMC2040341
115. Roe AH, McAllister A, Flynn AN, Martin B, Jiang E, Koelper N, et al. The effect of mifepristone pretreatment on bleeding and pain during medical management of early pregnancy loss. Contraception. 2021;104(4):432-436. doi:10.1016/j.contraception.2021.04.023 PMID: 33930380; PMC10302372
116. Miller KAR, de Castro Martin GC, Servidoni ACP, Dos Santos PL, Lemos MJ, Pereira H, et al. Comparative effectiveness of misoprostol plus letrozole versus misoprostol alone for pharmacological abortion: a systematic review and meta-analysis of randomized controlled trials. Eur J Contracept Reprod Health Care. 2026;31(4):320-335. doi:10.1080/13625187.2026.2636802 PMID: 41774466
117. Fikry Yousef M, Abdelfatah Sheeba M, Saad Amin Mohamed H, Adel Abdelmonem Salama A, Hassan A, Taghian M, et al. Efficacy and Safety of Letrozole, Misoprostol and Their Combination in First Trimester Missed Miscarriage: A randomised clinical trial. Sultan Qaboos Univ Med J. 2026;26(1):84-91. doi:10.18295/2075-0528.2962 PMID: 41659219; PMC12875326
118. Lemmers M, Verschoor MA, Hooker AB, Opmeer BC, Limpens J, Huirne JA, et al. Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis. Hum Reprod. 2016;31(1):34-45. doi:10.1093/humrep/dev274 PMID: 26534897
119. Hooker AB, Lemmers M, Thurkow AL, Heymans MW, Opmeer BC, Brölmann HA, et al. Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Hum Reprod Update. 2014;20(2):262-78. doi:10.1093/humupd/dmt045 PMID: 24082042
120. American College of Obstetricians and Gynecologists. ACOG Clinical Practice Update: Rh D immune globulin administration after abortion or pregnancy loss at less than 12 weeks of gestation. Obstet Gynecol. 2024;144(6):e140-e143. doi:10.1097/AOG.0000000000005733. PMID: 39255498
121. Sandhu NK, Wong AJ, Paulson RJ, Creinin MD. Current reproductive endocrinology and infertility practices regarding Rh-immune globulin administration in early pregnancy. F S Rep. 2026;7(1):86-89. doi:10.1016/j.xfre.2025.10.009. PMID: 41694259
122. Wong AJ, Paulson RJ. RhD immune globulin administration after early pregnancy loss following fertility treatment: time for national guidelines. F S Rep. 2025;6(4):409-410. doi:10.1016/j.xfre.2025.11.002. PMID: 41473571
123. Maurice P, Vigoureux S, Garabedian C, Sibiude J, Sananès N. Prevention of RhD alloimmunization in the first trimester of pregnancy: Clinical practice guidelines of the French College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2025;171(1):63-71. doi:10.1002/ijgo.70166. PMID: 40251923
124. Society for Maternal-Fetal Medicine. Electronic address: pubs@smfm.org, Prabhu M, Louis JM, Kuller JA, SMFM Publications Committee. Society for Maternal-Fetal Medicine Statement: RhD immune globulin after spontaneous or induced abortion at less than 12 weeks of gestation. Am J Obstet Gynecol. 2024;230(5):B2-B5. doi:10.1016/j.ajog.2024.02.288 PMID: 38417536
125. Gemzell-Danielsson K, Cameron S, Bombas T, Parachini M, Lubusky M, Agostini A, et al. Rhesus testing and anti-D prophylaxis in RhD-negative women undergoing first-trimester abortion—Systematic Review and Opinion. Int J Gynaecol Obstet. 2026;172(2):759-771. doi:10.1002/ijgo.70404. PMID: 40728267
126. Piltch G, Rochelson D, Rochelson B. Navigating drug shortages in obstetric care. O G Open. 2026;3(2):e156. doi:10.1097/og9.0000000000000156. PMID: 41767249
127. Coomarasamy A, Devall AJ, Cheed V, Harb H, Middleton LJ, Gallos ID, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. N Engl J Med. 2019;380(19):1815-1824. doi:10.1056/NEJMoa1813730 PMID: 31067371
128. United States District Court for the Western District of Louisiana. State of Louisiana et al. v. U.S. Food and Drug Administration et al., No. 6:25-cv-01491-DCJ-DJA. Federal Defendants' status report (Document 278). Filed 2026 Oct 7. Available from: https://litigationtracker.law.georgetown.edu/wp-content/uploads/2025/10/Louisiana_2026.10.07_DEFENDANTS-STATUS-REPORT.pdf
129. Schreiber CA, Creinin MD, Atrio J, Sonalkar S, Ratcliffe SJ, Barnhart KT. Mifepristone Pretreatment for the Medical Management of Early Pregnancy Loss. N Engl J Med. 2018;378(23):2161-2170. doi:10.1056/NEJMoa1715726 PMID: 29874535; PMC6437668
130. Chu JJ, Devall AJ, Beeson LE, Hardy P, Cheed V, Sun Y, et al. Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396(10253):770-778. doi:10.1016/S0140-6736(20)31788-8 PMID: 32853559; PMC7493715
131. Zhang J, Gilles JM, Barnhart K, Creinin MD, Westhoff C, Frederick MM, et al. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med. 2005;353(8):761-9. doi:10.1056/NEJMoa044064 PMID: 16120856
132. Ghosh J, Papadopoulou A, Devall AJ, Jeffery HC, Beeson LE, Do V, et al. Methods for managing miscarriage: a network meta-analysis. Cochrane Database Syst Rev. 2021;6(6):CD012602. doi:10.1002/14651858.CD012602.pub2 PMID: 34061352; PMC8168449
133. Okeke Ogwulu CB, Williams EV, Chu JJ, Devall AJ, Beeson LE, Hardy P, et al. Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial. BJOG. 2021;128(9):1534-1545. doi:10.1111/1471-0528.16737 PMID: 33969614
134. Petrou S, Trinder J, Brocklehurst P, Smith L. Economic evaluation of alternative management methods of first-trimester miscarriage based on results from the MIST trial. BJOG. 2006;113(8):879-89. doi:10.1111/j.1471-0528.2006.00998.x PMID: 16827823
135. Carp H, Toder V, Aviram A, Daniely M, Mashiach S, Barkai G. Karyotype of the abortus in recurrent miscarriage. Fertil Steril. 2001;75(4):678-82. doi:10.1016/s0015-0282(00)01801-x PMID: 11287018
136. Miscarriage UK (The Miscarriage Association) [Internet]. Wakefield (UK). Available from: https://www.miscarriageuk.org/
137. Share Pregnancy & Infant Loss Support [Internet]. Available from: https://nationalshare.org/
138. European Society of Human Reproduction and Embryology. Recurrent pregnancy loss — patient guideline (update 2022, final version January 2023). Available from: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss