Recurrent Miscarriage: Causes, Evaluation, and Treatment

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Medscape General Medicine. 1998;1(3) 

In This Article

Impact and Implications of Chromosomal Abnormalities


Chromosome imbalance caused by the absence or duplication of chromosomal material most often results in spontaneous abortion. In a live birth, chromosomal imbalance generally produces some phenotypic effect, most often congenital anomalies and mental retardation. There are 2 basic types of chromosomal imbalance: aberrations in chromosome numbers (numerical abnormalities) and defects in chromosome structure (structural anomalies). These can be diagnosed by cytogenetic study (karyotype analysis) of virtually any tissue type.

Numerical chromosomal abnormalities (aneuploidies) -- the presence of an extra chromosome (trisomy) or a missing chromosome (monosomy) -- result from segregation errors during cell division: Chromosomes do not divide evenly among daughter cells (nondisjunction) (see Fig. 2). For unknown reasons, trisomies are positively associated with advanced maternal age. Polyploidy refers to the presence of an extra set of chromosomes. Triploidy, for example, usually occurs when 2 spermatozoa fertilize an oocyte, resulting in a zygote that contains 3 sets of chromosomes instead of 2 (see Fig. 3). Numerical abnormalities are sporadic, and they do not usually recur in subsequent pregnancies.

Figure 2. (click image to zoom) Karyotype of 47,XX+16 (trisomy 16), most common trisomy associated with spontaneous abortion. Recurrence risk for chromosomal anomaly in subsequent pregnancy is 1% or less. (Arrow indicates extra chromosome.)
Figure 3. (click image to zoom) Karyotype of 69,XXY (triploidy), common finding in spontaneous abortion. Risk for chromosomal anomaly in subsequent pregnancy is not increased significantly.

Structural chromosomal anomalies are different from numerical anomalies in that they consist of a defect in the structure of 1 or more chromosomes. Examples include inversions (part of a chromosome is turned around), rings (a chromosome forms a ring structure), and translocations (parts of chromosomes in the wrong location). Translocations may be reciprocal or Robertsonian. In a reciprocal translocation, pieces from 2 nonhomologous chromosomes have switched places with each other; in a Robertsonian translocation, 2 acrocentric chromosomes -- that is, chromosomes with essentially a single long arm rather than the more normally encountered long and short arms -- are fused together. The acrocentric chromosomes are 13, 14, 24, 15, 21, and 22. In a balanced structural chromosomal anomaly the amount of chromosomal material present is normal, but the configuration is abnormal. An individual carrying a balanced rearrangement would usually not have any phenotypic effect, except for the possibility of impaired fertility and reproduction.

Structural chromosomal abnormalities occur in about 1 of 500 persons. These structural defects may be passed from parent to child; therefore, when a structural anomaly (balanced or unbalanced) is found in a fetus or in an individual, karyotype analysis of parents and possibly other relatives is indicated.

Relationship to Spontaneous Abortion

Chromosomal anomalies are known to be the single most common cause of spontaneous abortion. Historically, 50% of spontaneously expelled abortuses have been thought to be chromosomally abnormal.[1]However, this is probably an underestimate in light of recent improvements in tissue culture techniques, coupled with earlier diagnosis of miscarriage.[2] In spontaneous abortions, the majority of chromosomal anomalies (95%) are numerical. About 60% are trisomies, trisomy 16 being the most common (see Fig. 2).[1] A further 20% are found to have 45,X (Turner's syndrome).[1]Interestingly, approximately 99% of fetuses with 45,X are expelled spontaneously.[3] Another 15% have polyploidy, especially triploidy (see Fig. 3).[1]

In the case of a numerical chromosomal anomaly in a fetus, parental chromosomes are usually normal, so karyotype analysis of the parents is not indicated. The recurrence risk for a chromosomal anomaly following the diagnosis of trisomy in a pregnancy is thought to be about 1%.[1,4]

After diagnosis of a numerical chromosomal anomaly, couples should be counseled about the 1% risk for recurrence of a numerical anomaly, and prenatal diagnosis of the fetus may be considered for any future pregnancies. On the other hand, if a structural chromosomal anomaly is found in a fetus, parental karyotypes are indicated. The presence of a balanced chromosomal rearrangement in a parent would result in an increased recurrence risk for structural chromosomal defects in future pregnancies.

Role of Chromosomal Anomalies in Recurrent Spontaneous Abortion

In up to 7% of couples with at least 2 spontaneous abortions, one partner carries a balanced chromosome rearrangement.[5] The most common of these is a reciprocal translocation in which a segment of chromosome has exchanged places with a segment of a nonhomologous chromosome. When such a rearrangement is present, the chromosomes have difficulty pairing up and dividing evenly during meiosis. As a result, gametes frequently possess an unbalanced amount of chromosomal material (duplications and/or deficiencies). These imbalances are usually lethal to the developing embryo or fetus, causing spontaneous abortion. Sometimes, the pregnancy continues to term, producing an infant with significant congenital anomalies and mental retardation.

When a parent carries a balanced chromosome rearrangement, the chance of having a live birth with an unbalanced chromosome complement is usually about 1% to 15%. The exact risk depends on the specific chromosomes involved, size of the segment(s) involved in the rearrangement, sex of the transmitting parent, family history, and mode of ascertainment. Therefore, it is quite possible that the couple will have healthy children. In fact, Coulam[6] found a higher incidence of chromosome rearrangement in couples who had experienced both recurrent spontaneous abortion and viable pregnancies than in couples with recurrent spontaneous abortion and no viable pregnancies. When 1 parent carries a chromosome rearrangement, the chance of spontaneous abortion is usually 25% to 50%. Empirical and/or hypothetical data are available for predicting the chance of adverse pregnancy outcome for various rearrangements.[1,7]

Relevance of Family History

When a patient presents having had recurrent spontaneous abortions, a detailed family history should be obtained, including information about the partner's family. The family history may provide a clue to the presence of a familial chromosome rearrangement. A history of any congenital anomaly, mental retardation, infertility, spontaneous abortion, or perinatal death is significant because each is characteristic of chromosomal anomaly (see Fig. 4).

Figure 4. (click image to zoom) Family pedigree showing typical features of familial chromosome rearrangement. In this family, husband had mentally retarded sister and brother whose wife suffered 2 spontaneous abortions. Family history is noteworthy, particularly in view of couple's experience having spontaneous abortion and stillbirth with growth retardation. Blood chromosome study of both partners is necessary to rule out translocation or other chromosomal anomaly.

Cytogenetic Studies of Abortuses

In determining the cause of fetal loss, it is useful to conduct a chromosome study on the abortus. Chromosome analysis is indicated in the case of a stillbirth or neonatal death because chromosomal anomalies are found in approximately 6% of these cases.[8] Tissues for cytogenetic studies should be obtained using sterile technique, and they should be delivered immediately to the cytogenetics laboratory in transport medium provided by the laboratory. If such medium is not available, a laboratory technician can provide information regarding the suitability of sterile saline or other solutions, although culture success is compromised. To avoid this problem, it is important to have tubes of frozen, unexpired transport medium onsite.

Tissue specimens that have been frozen or placed in formalin may not be cultured. Tissues suitable for cytogenetic study include placental villi, chorion, amnion, skin, or internal organs such as liver, lung, kidney, or spleen. For early gestation, the entire abortus may be submitted. For later gestation, blood in a sodium heparin tube is also suitable. Submitting several specimen types increases the culture success rate which, even in laboratories with the most experienced staff, is usually no more than 85%.

Cytogenetic Studies of Parents

When a couple has had 2 or more spontaneous abortions or a child with a structural chromosomal anomaly, chromosomal analysis on both partners should be considered. Analysis requires a 5mL to 10mL blood sample in a tube with sodium heparin.

The chance of a balanced chromosome rearrangement in 1 partner of a couple with 2 or more spontaneous abortions is about 7%.[5] Determining the presence of such a rearrangement in a parent is useful because it provides: (1) an explanation for the miscarriages; (2) information about the risk for a live-born child with potentially serious anomalies, as well as the risk for future miscarriages; (3) availability of prenatal diagnosis in a future pregnancy; and (4) information for members of the extended family who may be at risk and may wish to undergo chromosome testing.

Genetic Counseling

Couples in which 1 partner is found to have a chromosomal rearrangement may benefit from genetic counseling. Counseling should include: (1) an explanation of the findings; (2) associated risks for miscarriage and live birth with phenotypic anomalies; and (3) a discussion of reproductive options, including prenatal diagnosis (amniocentesis or chorion villus sampling), donor insemination (if the husband is the carrier) or egg donor (if the wife is the carrier). Implications for the extended family would also be discussed, and assistance would be provided in informing relatives.

Genetic counseling is best provided before the next pregnancy, so all options may be explored and appropriate planning may be instituted. Although a minority of couples elect not to have biologic children in this situation, the majority are relieved to find out that the chance of having a healthy child is high. Genetic counselors can be located through the National Society of Genetic Counselors.