Key Abbreviations
American College of Obstetricians and Gynecologists ACOG
Anticardiolipin aCL
Antiphospholipid antibody aPL
Assisted reproductive technology ART
β-Human chorionic gonadotropin β-hCG
Bacterial vaginosis BV
Cesarean delivery CD
Comparative genomic hybridization CGH
Confidence interval CI
Fluorescence in situ hybridization FISH
Human chorionic gonadotropin hCG
In vitro fertilization IVF
Low birthweight LBW
Lupus anticoagulant LAC
Luteal phase deficiency LPD
National Institute of Child Health and Human Development NICHD
Preimplantation genetic diagnosis PGD
Recurrent early pregnancy loss REPL
Recurrent miscarriage RM
Royal College of Obstetricians and Gynaecologists RCOG
Small for gestational age SGA
Standard deviation SD
Three-dimensional 3-D
Thyroid receptor beta TR-β
Thyroid-stimulating hormone TSH
Very low birthweight VLBW
Very preterm delivery VPTD
Not all conceptions result in a live-born infant, and human reproduction is extremely inefficient compared with that of other mammal species. About 50% to 70% of spontaneous conceptions are lost before completion of the first trimester, most before implantation or during the first month after the last menstrual period. These losses are often not recognized as conceptions. Of clinically recognized pregnancies, 10% to 15% are lost. Although epidemiologic data are limited on animals living in the wild, such as monkeys, laboratory rodents are known to have postimplantation pregnancy loss rates of less than 10%. Among married women in the United States, 4% have experienced two fetal losses, and 3% have experienced three or more. A subset of women manifest repetitive spontaneous miscarriages, as opposed to randomly having repeated untoward events. This chapter considers the frequency and timing of pregnancy losses, the causes of fetal wastage, and the management of couples who experience repetitive losses.
Frequency and Timing of Pregnancy Loss
Embryos implant 6 days after conception, although physical signs are not generally appreciated until 5 to 6 weeks after the last menstrual period. Fewer than half of preimplantation embryos persist, as witnessed by assisted reproductive technology (ART) success rates rarely exceeding 30% to 40% of cycles initiated; even after implantation, judged preclinically by the presence of β-human chorionic gonadotropin (β-hCG), about 30% of pregnancies are lost. After clinical recognition, 10% to 12% are lost. Most clinical pregnancy losses occur before 8 weeks. Before widespread availability of ultrasound, embryonic demise was often not appreciated until 9 to 12 weeks’ gestation, at which time bleeding and passage of tissue (products of conception) occurred. With widespread availability of ultrasound, it has been shown that fetal demise actually occurs weeks before overt clinical signs are manifested. This conclusion was reached on the basis of cohort studies that showed that only 3% of viable pregnancies are lost after 8 weeks’ gestation ; studies involving obstetric registrants reached similar conclusions. Fetal viability thus ceases weeks before maternal symptoms of pregnancy loss. That almost all losses are retained in utero for some time before clinical recognition means that virtually all losses could be considered “missed abortions,” thus this once widely used term is actually archaic.
After the first trimester, pregnancy losses occur at a slower rate. Loss rates are only 1% in women confirmed by ultrasound to have viable pregnancies at 16 weeks. Two confounding factors that influence clinical pregnancy loss rates are clinically relevant: maternal age is positively correlated with pregnancy loss rates, and a 40-year-old woman has twice the risk of a 20-year-old woman. This occurs in euploid and aneuploid pregnancies, as discussed later. Prior pregnancy loss also increases loss rates, but far less than once believed. Among nulliparous women who have never experienced a loss, the likelihood of pregnancy loss is only 5% to 10% ( Table 27-1 ). After one loss, the risk of another is increased but does not exceed 30% to 40% even for women with three or more losses. These risks apply not only to those women whose losses were recognized at 9 to 12 weeks’ gestation but also to those whose pregnancies were ascertained in the fifth week of gestation. Of clinical relevance, no scientific evidence suggests that women with three losses are etiologically distinct from those with two losses or even one loss. The situation may be different if four or more losses have occurred, and different etiologic factors may exist in this uncommon subgroup.
| PRIOR SPONTANEOUS ABORTIONS | RISK (%) | |
|---|---|---|
| Women with liveborn infant | 0 | 5-10 |
| 1 | 20-25 | |
| 2 | 25 | |
| 3 | 30 | |
| 4 | 30 | |
| Women without liveborn infant | 3 | 30-40 |
The clinical consequence of the above information is that in order to be judged efficacious in preventing recurrent first-trimester spontaneous abortions, therapeutic regimens must show success rates substantially greater than 70%. Essentially no therapeutic regimen can make this claim.
Placental Anatomic Characteristics of Successful and Unsuccessful Pregnancies
As judged by adult tissue criteria, the human fetus develops in a low-oxygen environment. Development of the human placenta is modulated heavily by the intrauterine environment. During the first trimester, development takes place in a low-oxygen environment supported by histotrophic nutrition from the endometrial glands. Consequently, the rate of growth of the chorionic sac is almost invariable across this period and is remarkably uniform among individuals. Toward the end of the first trimester, the intrauterine environment undergoes radical transformation in association with onset of the maternal arterial circulation and the switch to hemotrophic nutrition ( Chapter 1 ). The accompanying rise in intraplacental oxygen concentration poses a major challenge to placental tissues, and extensive villous remodeling takes place at this time.
The human gestational sac is designed to minimize the flux of oxygen (O 2 ) from maternal blood to the fetal circulation. In particular, the extravillous trophoblast that migrates inside the uterine tissue to anchor the pregnancy creates a cellular shell with plugs inside the tip of the uteroplacental arteries. This additional barrier keeps most of the maternal circulation outside the placenta and thus reduces the chemical activity of free oxygen radicals inside the placenta during most of the first trimester of the human pregnancy. In normal pregnancies, the onset of the maternal circulation is a progressive phenomenon that starts at about 9 weeks at the periphery of the placenta and gradually extends toward the center. This process correlates closely with the pattern of trophoblast invasion across the placental bed ( Fig. 27-1 ).
In about two thirds of early pregnancy failures, anatomic evidence of defective placentation is apparent, which is mainly characterized by a thinner and fragmented trophoblast shell and reduced cytotrophoblast invasion of the lumen at the tips of the spiral arteries. This is associated with premature onset of the maternal circulation throughout the placenta in most cases of miscarriages. These defects are similar in euploid and in most aneuploid miscarriages but are more pronounced in hydatidiform moles ( Fig. 27-2 ). In vivo ultrasound and histopathologic data indicate that in most early pregnancy losses, the onset of the intervillous circulation is premature and widespread owing to incomplete transformation and plugging of the uteroplacental arteries. In about 80% of missed miscarriages, the onset of the maternal placental circulation is both precocious and generalized throughout the placenta. This occurs independent of the karyotype of the conceptus, leading to higher O 2 concentrations during early pregnancy, widespread trophoblastic oxidative damage, and placental degeneration. Although in vitro studies have demonstrated the ability of damaged syncytium to regenerate from the underlying cytotrophoblast, it is likely that in the face of extensive damage, this ability will be overwhelmed, leading to complete pregnancy failure.
Numerical Chromosomal Abnormalities: the Most Frequent Cause of Early Pregnancy Loss
Chromosomal abnormalities are the major cause of both preimplantation and clinically recognized pregnancy loss. Of all morphologically normal embryos, 25% to 50% show chromosomal abnormalities (aneuploidy or polyploidy). The highest figure occurs in women over age 45, and a more generalizable figure is 25% in the third decade increasing to 50% by late in the fourth decade. The frequency of chromosomal abnormalities in morphologically abnormal embryos is even higher. The high aneuploidy rate in morphologically normal embryos is consistent with 5% to 10% aneuploidy in sperm of ostensibly normal men and 20% aneuploidy in oocytes (deduced from polar bodies) of women undergoing ART.
Not surprisingly, at least 50% of clinically recognized pregnancy losses result from a chromosomal abnormality. The frequency is probably higher, because if chorionic villi recovered by chorionic villus sampling (CVS) are analyzed immediately after ultrasound diagnosis of fetal demise, rather than culturing spontaneously expelled products, the chromosomal abnormalities are detected in 75% to 90%. However, these cohorts were older than the general population.
Among second-trimester and third-trimester losses, chromosomal abnormalities are more similar in type to those observed in live-born infants: trisomies 13, 18, and 21; monosomy X; and sex chromosomal polysomies. This also holds true among losses after 20 gestational weeks (stillborn infants), for which the frequency of chromosomal abnormalities detected by karyotype has traditionally been cited as approximately 5%. The frequency is over 20% if anatomic abnormalities are present and chromosomal microarray (comparative genomic hybridization [CGH]) is used because cell culture is not needed to obtain information. The American College of Obstetricians and Gynecologists (ACOG) now recommends array CGH for this purpose. Of stillborn infants, 8.3% show cytogenomic abnormalities such as aneuploidy, microdeletions or microduplication based on array CGH, and copy number variants versus 5.8% by karyotype. Overall, the frequency of demonstrable abnormalities is much less than that observed in earlier abortuses but is much higher than that found among liveborn infants (0.6%). Formal recommendations for the management of couples who have had a stillborn infant is undertaken later in this chapter.
Types of Numerical Chromosomal Abnormalities
Autosomal Trisomy
Autosomal trisomies represent the largest single class (about 50%) of chromosomal complements in cytogenetically abnormal spontaneous abortions. That is, 25% of all abortuses are aneuploid, given half of all abortuses have a chromosomal abnormality. Frequencies of various trisomies are listed in Table 27-2 . Trisomy for every chromosome has been observed, but the most common is trisomy 16, which is lethal and is not observed in liveborn infants. Most trisomies show a maternal age effect, but the effect varies markedly among chromosomes. The increased maternal age effect is especially impressive for double trisomies.
| CHROMOSOMAL COMPLEMENT | FREQUENCY | PERCENT |
|---|---|---|
| Normal 46,XX or 46,XY | 54.1 | |
| Triploidy: | 7.7 | |
| 69,XXX | 2.7 | |
| 69,XYX | 0.2 | |
| 69,XXY | 4.0 | |
| Other | 0.8 | |
| Tetraploidy: | 2.6 | |
| 92,XXX | 1.5 | |
| 92,XXYY | 0.55 | |
| Not stated | 0.55 | |
| Monosomy X | 18.6 | |
| Structural abnormalities | 1.5 | |
| Sex chromosome polysomy: | 0.2 | |
| 47,XXX | 0.05 | |
| 47,XXY | 0.15 | |
| Autosomal monosomy (G) | 0.1 | |
| Autosomal trisomy for chromosomes: | 22.3 | |
| 1 | 0 | |
| 2 | 1.11 | |
| 3 | 0.25 | |
| 4 | 0.64 | |
| 5 | 0.04 | |
| 6 | 0.14 | |
| 7 | 0.89 | |
| 8 | 0.79 | |
| 9 | 0.72 | |
| 10 | 0.36 | |
| 11 | 0.04 | |
| 12 | 0.18 | |
| 13 | 1.07 | |
| 14 | 0.82 | |
| 15 | 1.68 | |
| 16 | 7.27 | |
| 17 | 0.18 | |
| 18 | 1.15 | |
| 19 | 0.01 | |
| 20 | 0.61 | |
| 21 | 2.11 | |
| 22 | 2.26 | |
| Double trisomy | 0.7 | |
| Mosaic trisomy | 1.3 | |
| Other abnormalities or not specified | 0.9 | |
| 100.0 |
Trisomies incompatible with life predictably show slower growth than those compatible with life (e.g., trisomies 13, 18, 21); but otherwise, usually no features distinguish the two groups. Abortuses from the former group may show anomalies consistent with those found in full-term, liveborn trisomic infants. Malformations present have been said to be more severe than those observed in induced abortuses following prenatal diagnosis.
Attempts have been made to correlate placental morphologic abnormalities with specific trisomies, but these relationships are imprecise. Comparison of ultrasound findings and placental histology indicates that villous changes following in utero fetal demise could explain the low predictive value of placental histology in identifying aneuploidy or another nonchromosomal etiology. By contrast, the histologic features of complete and partial hydatidiform molar gestations are so distinctive that most molar miscarriages can be correctly diagnosed by histologic examination alone.
Aneuploidy usually results from errors at maternal meiosis I, and these are associated with advanced maternal age. Once thought to involve mostly missegregation of whole chromosomes, it is now clear that chromatid errors are an equally prevalent cause of maternal meiotic errors. The cytologic mechanism involves decreased or absent meiotic recombination. The cytologic origin is not the same for all chromosomes. In trisomy 13 and trisomy 21, 90% to 95% of these maternal cases arise at meiosis I; almost all trisomy 16 cases arise in maternal meiosis I. In trisomy 18, two thirds of the 90% of maternal meiotic cases arise at meiosis II.
One practical consequence of the maternal origin of aneuploidy is that deducing the chromosomal status of oocytes is possible by analysis of the polar bodies. In preimplantation genetic diagnosis, the most common approach is now blastocyst biopsy (5-day embryo), but diagnosis based on the first polar body uniquely allows preconception assessment, which in certain cultures or venues is the only option ( Chapter 10 ). Errors in paternal meiosis account for 10% of acrocentric (13, 14, 15, 21, and 22) trisomies. Among nonacrocentric chromosomes, paternal contribution is uncommon.
Polyploidy
In polyploidy, more than two haploid chromosomal complements are present. Nonmosaic triploidy (3n = 69) and tetraploidy (4n = 92) are common in abortuses. Triploid abortuses are usually 69,XXY or 69,XXX as a result of dispermy. An association exists between diandric (paternally inherited) triploidy and hydatidiform mole, a “partial” mole said to exist if molar tissue and fetal parts coexist. The more common “complete” (classic) hydatidiform mole is 46,XX; androgenetic in origin; and composed exclusively of villous tissue. Pathologic findings in diandric triploid and tetraploid placentae include a disproportionately large gestational sac, focal (partial) hydropic degeneration of placental villi, and trophoblast hyperplasia. Placental hydropic changes are progressive and may be difficult to identify in early pregnancy. By contrast, placental villi often undergo hydropic degeneration after fetal demise. This can occur in all types of miscarriage; thus histologic and cytogenetic investigations are essential to differentiate between true mole and pseudomole because only a true mole can be associated with persistent trophoblastic disease. Fetal malformations associated with triploid miscarriage include neural tube defects and omphaloceles, anomalies reminiscent of those observed in triploid conceptuses that survive to term. Facial dysmorphia and limb abnormalities have also been reported. Tetraploidy is uncommon and rarely progresses beyond 2 to 3 weeks of embryonic life. This chromosomal abnormality can also be associated with persistent trophoblastic disease and thus needs to be identified in order to offer human chorionic gonadotropin (hCG) follow-up.
Sex Chromosome Polysomy (X or Y)
The complements 47,XXY and 47,XYY have long been stated to occur in about 1 per 800 liveborn male births; 47,XXX occurs in 1 per 800 female births. X and Y polysomies are only slightly more common in abortuses than in live-born infants. Recent work based on cell-free fetal DNA for detection of certain autosomal trisomies and sex chromosome polysomies indicates the incidence of the latter may be less than traditionally stated. Irrespective, the group is not a major contributor to spontaneous abortion.
Monosomy X
Monosomy X is the single most common chromosomal abnormality among spontaneous abortions, accounting for 15% to 20% of abnormal specimens (see Table 27-2 ). Monosomy X embryos usually consist of only an umbilical cord stump. Later in gestation, anomalies characteristic of Turner syndrome may be seen, such as cystic hygromas and generalized edema ( Fig. 27-3 ). Unlike adult 45,X individuals, 45,X abortuses show germ cells; however, most germ cells in abortuses do not develop beyond the primordial germ cell stage. The pathogenesis of 45,X germ cell failure thus involves not so much failure of germ cell development as more rapid attrition in 45,X compared with 46,XX embryos. Monosomy X usually occurs (80%) as a result of paternal sex chromosome loss, consistent with lack of a maternal age effect.
Relationship Between Recurrent Losses and Numerical Chromosomal Abnormalities
In both preimplantation and first-trimester abortions, recurrent aneuploidy occurs more often than would be expected by chance. Recurrent aneuploidy is a frequent explanation, at least until the number of losses reaches or exceeds four. In a given family, successive abortuses are likely to be either recurrently normal or recurrently abnormal. Table 27-3 shows that if the complement of the first abortus is abnormal, recurrence usually involves aneuploidy, although not necessarily of the same chromosome. Further supporting recurrent aneuploidy as a genuine phenomenon is the occurrence of trisomic preimplantation embryos in successive ART cycles.
| COMPLEMENT OF FIRST ABORTUS | COMPLEMENT OF SECOND ABORTUS | |||||
|---|---|---|---|---|---|---|
| Normal | Trisomy | Monosomy | Triploidy | Tetraploid | De Novo Rearrangement | |
| Normal | 142 | 18 | 5 | 7 | 3 | 2 |
| Trisomy | 31 | 30 | 1 | 4 | 3 | 1 |
| Monosomy X | 7 | 5 | 3 | 3 | 0 | 0 |
| Triploidy | 7 | 4 | 1 | 4 | 0 | 0 |
| Tetraploidy | 3 | 1 | 0 | 2 | 0 | 0 |
| De novo rearrangement | 1 | 3 | 0 | 0 | 0 | 0 |
The concept of recurrent aneuploidy implies certain corollaries, one of which has often been the subject of controversy. One is that in recurrent losses, couples should either be experiencing repetitive chromosomally abnormal abortuses or repetitive euploid (chromosomally normal) abortuses. Given that 50% of all abortuses are abnormal cytogenetically, aneuploidy should be as likely to be detected in a randomly karyotyped abortus as in a sporadic abortus. Among 420 abortuses obtained from women with repeated losses, Stephenson and colleagues found 46% had chromosomal abnormalities; 31% of the original sample was trisomic. Their comparison was unselected pooled data, which showed 48% of abortuses to be abnormal; 27% of the original sample was trisomic.
In contrast to these data, a fetal loss—recurrent or not—is much more likely to be cytogenetically normal (85%) when it occurs after the first trimester. Carp and coworkers found that among women with three or more abortuses, the likelihood that the abortus would have an abnormal karyotype was only 29%. However, in that series, inclusion criteria extended to 20 weeks’ gestation, a time at which there is less reason to expect recurrent aneuploidy than recurrence of other etiologies.
Genetic Counseling and Management for Recurrent Aneuploidy
Couples predisposed to recurrent aneuploidy are at increased risk not only for aneuploid abortuses but also for aneuploid liveborn neonates. The trisomic autosome in a subsequent pregnancy might be compatible with life (e.g., trisomy 21). Indeed, the risk for liveborn trisomy 21 following an aneuploid abortus is considered clinically to be about 1% (see Chapter 10 ). A 1% recurrence risk is considered similar following other autosomal aneuploidies. Bianco and associates provided a useful counseling algorithm applicable following a prior abortion of unknown karyotype. If abortions are recurrent but no information is available on the chromosomal status, the odds ratio can be used to derive a patient-specific risk. For example, if the a priori Down syndrome risk is 1 in 300 and the odds ratio is 1.5, a woman’s calculated risk after three abortions would be 1/300 × 1.5, or 1 in 200.
If no information is available concerning the chromosomal status of prior abortuses, paraffin blocks of archived products of conception can be retrieved to detect aneuploidy using array CGH, given that array CGH requires only DNA and not the cultured cells needed for a karyotype. Paraffin block or results of other archived DNA showing a prior trisomy confers increased risk for liveborn trisomy in subsequent pregnancies. If no information can be obtained, it is arguable whether prenatal genetic diagnosis is appropriate. The absolute risk for aneuploid offspring can, however, be calculated as shown by Bianco and associates. The small but finite risk for amniocentesis or CVS is troublesome to couples who have had difficulty achieving a live birth. At present, noninvasive cell-free DNA approaches (see Chapter 10 ) are typically the chosen option. However, sensitivity for detecting aneuploidy by noninvasive methods is not the nearly 100% possible with CVS or amniocentesis. Preimplantation genetic diagnosis (PGD; see Chapter 10 ) is another option, and it is the only one if the couple eschews clinical pregnancy termination. Selective transfer of euploid embryos clearly decreases the rate of clinical abortions in couples who experience repeated losses. When avoiding another loss is paramount, PGD should be offered.
Chromosomal Rearrangements
Translocations
Structural chromosomal abnormalities are an unequivocal explanation for repetitive abortions. The most common structural rearrangement encountered is a translocation, found in about 5% of couples who experience repeated losses. Individuals with balanced translocations are phenotypically normal, but their offspring—abortuses and abnormal liveborn infants—may show chromosomal duplications or deficiencies as a result of normal meiotic segregation. Among couples with repetitive abortions, about 60% of translocations are reciprocal and 40% are robertsonian. Women are about twice as likely as men to show a balanced translocation.
The clinical consequences of a balanced translocation vary depending on the chromosome involved and the type of translocation. If a child has Down syndrome as result of a centric fusion (robertsonian) translocation, the rearrangement will have originated de novo in 50% to 75% of cases. That is, a balanced translocation will not exist in either parent. The likelihood of Down syndrome recurring in subsequent offspring is minimal. On the other hand, the recurrence is significant when an offspring has Down syndrome as result of transmission of a parental translocation. The theoretic risk for having a child with Down syndrome is 33%, but empiric risks are considerably less. The risk is only 2% if the father carries the translocation; the risk is 10% if the mother carries the translocation. If robertsonian (centric fusion) translocations involve chromosomes other than 21, liveborn empiric risks are lower; this reflects embryonic lethality. In t(13q;14q), the risk for liveborn trisomy 13 is 1% or less.
Reciprocal translocations involve not centromeric fusion but rather interchanges between two or more chromosomes. Empiric data for specific translocations are usually not available, but generalizations can be made on the basis of pooled data derived from many different translocations. Again, theoretic risks for abnormal offspring (unbalanced reciprocal translocations) are far greater than empiric risks applicable to liveborn infants or even prenatal genetic diagnosis. Overall, the risk is 12% for offspring of either female heterozygotes or male heterozygotes. Detecting a chromosomal rearrangement thus profoundly affects subsequent pregnancy management. Antenatal cytogenetic studies should be offered. The frequency of unbalanced fetuses is lower if parental balanced translocations are ascertained through repetitive abortions (3%) rather than through anomalous liveborn infants (nearly 20%). Presumably more unbalanced products are lethal.
PGD of embryos from couples who have a balanced translocation reveals that most embryos are unbalanced: 58% in robertsonian translocations and 76% in reciprocal translocations. This means almost all these conceptuses would be lost preclinically. When a balanced translocation is detected in a couple who experiences recurrent abortions, the cumulative prognosis for a liveborn infant differs little from that if a translocation had not been detected. However, the length of time to achieve pregnancy is greatly increased (mean, 4 to 6 years). Thus a more realistic strategy is to use PGD to identify and transfer only the few balanced embryos, thereby increasing the statistical likelihood of conception. This strategy is most attractive when the prospective mother is in her fourth or early fifth decade. Using array CGH, an unbalanced embryo can be readily excluded; however, unlike fluorescence in situ hybridization (FISH), array CGH does not distinguish a balanced (translocation heterozygote) from a normal embryo lacking the translocation.
Rarely, a translocation precludes normal liveborn infants. This occurs when a translocation involves homologous, acrocentric chromosomes (e.g., t[13q13q] or t[21q21q]). If the father carries such a structural rearrangement, artificial insemination may be appropriate. If the mother carries the rearrangement, donor oocytes or donor embryos and ART should be considered.
Inversions
Inversions are uncommon parental chromosomal rearrangements but are responsible for repetitive pregnancy losses analogous to translocations. In inversions, the order of the genes is reversed. Individuals heterozygous for an inversion should be normal if their genes are merely rearranged. However, individuals with inversions suffer untoward reproductive consequences as a result of normal meiotic phenomena. Crossing over that involves the inverted segment yields unbalanced gametes. Pericentric inversions are present in perhaps 0.1% of women and 0.1% of men who experience repeated spontaneous abortions. Paracentric inversions are even rarer.
Women with a pericentric inversion have a 7% risk for abnormal liveborn infants; men carry a 5% risk. Pericentric inversions ascertained through phenotypically normal probands are less likely to result in abnormal liveborn infants. Inversions that involve only a small portion of the total chromosomal length paradoxically are less significant clinically because large duplications or deficiencies arise following crossing over, which usually confers lethality. By contrast, inversions that involve only 30% to 60% of the total chromosomal length are relatively more likely to be characterized by duplications or deficiencies compatible with survival. Prenatal cytogenetic studies should be offered.
Paracentric inversions should carry less risk for unbalanced products than pericentric inversions because nearly all paracentric recombinants should in theory be lethal. However, abortions and abnormal liveborn infants have rarely been observed within the same kindred, and the risk for unbalanced viable offspring has been tabulated at 4%. Prenatal cytogenetic studies should thus still be offered.
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