ABSTRACT
The first report of a chromosomal abnormality in aborted material was of a triploidy in spontaneous abortion, four decades ago by Penrose and Delhanty.1 It took several years before cytogenetic analysis of miscarriage became an option in laboratories, due to the difficulties of culturing fetal tissue. The development of techniques, which allowed chorionic villi to be used for “long-term cultures,” and later “direct preparation of metaphases from villi,” revolutionized the cytogenetic analysis of products of conception. Since then it is debatable whether it is either clinically justifiable or psychologically essential to determine the cause of pregnancy loss for counseling about further pregnancies. The crucial role of chromosomal imbalance in abnormal early human development is well established. It has been suggested that most chromosome abnormalities result in disordered development incompatible with prolonged intrauterine survival and live birth. The mechanism by which a chromosome abnormality could lead to regression of the conceptus is unclear. Approximately 50−60% of first trimester spontaneous abortions have karyotypic abnormalities, mainly numerical such as autosomal trisomy, monosomy X, and polyploidy. This conclusion is based on the results of cytogenetic studies conducted in laboratories throughout the world.2 The majority (90%) of karyotypically abnormal pregnancies miscarry in the first trimester, and the majority (93%) of karyotypically normal pregnancies continue.3 Most chromosomal abnormalities that result in spontaneous abortion are random events, and may be associated with recurrent spontaneous abortion. However, even in recurrent spontaneous miscarriage, parental carriership is found in 4-6%.4-5
Cytogenetic evaluation of sporadic spontaneous abortions has shown that 50-60% are chromosomally abnormal. This means that about 5-10.5% of all pregnancies result in sporadic abortions caused by chromosomal abnormalities. Pregnancy loss of chromosome origin is uncommon after 15 weeks gestation; therefore, this chapter concentrates on first trimester miscarriages. Fetal de novo chromosomal abnormalities are a major cause of sporadic first trimester spontaneous abortions, and some cases of recurrent miscarriage might be caused by repeat fetal chromosomal abnormalities. Although tissue sampling, culture technique, and direct preparation of chorionic villi have improved over time, the rate of chromosomal abnormality has remained similar with a detection rate of 49%. Numerical abnormalities are found in approximately 86% of these, with trisomies being the most frequent (52%) (trisomies 6, 13, 18, 21, and 22), followed by polyploidy (21%) and monosomy X (13%). Structural chromosome abnormalities can be classified as deletions, translocations, inversions, and duplications, but only translocations and inversions play a role in miscarriages. Structural chromosome abnormalities occur in less than 5% of chromosomally abnormal abortuses. In approximately 8% of cases, other chromosome abnormalities are found including double and triple trisomies (accounting for about 1.4% and 0.05%, respectively). These figures have remained constant over time, and independent of the culture method used or the success rate, which is now reported to be approximately 90%.2,4,6 The recurrence risk of another miscarriage is not, or only slightly elevated (16%) when compared to the initial risk for all women (10-15%), and thus
routine karyotyping of fetal material in miscarriages is thought not to be worthwhile and unnecessary.4 Furthermore, it should be noted that karyotyping of abortuses has many pitfalls including the possibility of maternal tissue contamination, failure to seek other causes of RPL if cytogenetic assessment reveals an abnormal karyotype and the occurrence of non-cytogenetic embryonic abnormalities.7 The recurrence risk of numerical abnormalities is low, so karyotyping of fetal material in case of a miscarriage does not seem to be worthwhile in daily practice. Half of the structural abnormalities may be inherited from a parent carrying a balanced chromosome translocation or inversion. This type of chromosomal abnormality would be found by parental karyotyping, however, based on the published literature, opinions are still divided regarding the incidence of carrier status, and if it is higher after three miscarriages rather than after two miscarriages. The Royal College of Obstetricians and Gynaecologists8 recommends chromosome analysis after three miscarriages, whereas the American Society of Reproduction Medicine,9 recommends chromosome analysis after two miscarriages. However, parental karyotyping is expensive and does not always give valuable information; therefore, its use could also be avoided in many couples.10-11
The presence of a cytogenetic abnormality in miscarriages explains the loss. However, in most couples with recurrent pregnancy loss, thorough evaluation, including parental karyotype testing will be negative. Therefore, the majority (approximately 50-75%) of couples with recurrent pregnancy loss have no definitive diagnosis. Live birth rates of between 35% and 85% are commonly reported in couples with unexplained recurrent pregnancy loss who undergo an untreated or placebo-treated subsequent pregnancy. Meta-analysis of randomized, prospective studies suggests that 60-70% of women with unexplained recurrent pregnancy loss will have a successful next pregnancy.12 Recurrent pregnancy loss may be due to an abnormal embryo, which is incompatible with life. As the number of miscarriages increases, the prevalence of chromosomal abnormality decreases, and the chance of recurring maternal cause increases.13-14
Thus, many couples will view the prognosis as favorable.
