An interesting medical overview of miscarriage

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Most spontaneous miscarriages are caused by an abnormal (aneuploid) karyotype of the embryo. At least 50% of all first-trimester SABs are cytogenetically abnormal. (Note that this figure does not include abnormalities caused by single genetic disorders, such as Mendelian disorders or mutations at several loci. Examples are polygenic or multifactorial disorders that are not detected by evaluating karyotypes.)

The highest rate of cytogenetically abnormal concepti occurs earliest in gestation, with rates declining after the embryonic period (>30 mm crown-rump length). The rate of normal (euploid) and abnormal (aneuploid) abortuses increases with maternal age.

Recurrent miscarriage may result from 2 chromosomal abnormalities: (1) a structural abnormality derived from 1 parent or (2) the recurrence of a numerical abnormality, which is usually not inherited.

Aneuploidy

Cytogenetically abnormal embryos are usually aneuploid because of sporadic events, such as meiotic nondisjunction, or polyploid from fertilization abnormalities. One half the cytogenetically abnormal abortuses in the first trimester involve autosomal trisomy. Triploidy is found in 16% of abortions, with fertilization of a normal haploid ovum by 2 sperm (dispermy) as the primary pathogenic mechanism. Trisomies may arise de novo because of meiotic nondisjunction during gametogenesis in parents with a normal karyotype. For most trisomies, maternal meiosis I errors have been implicated. Abnormal meiotic segregation results in either complete trisomies or monosomies.

Trisomy 16, which accounts for 30% of all trisomies, is the most common. Viable trisomies have been observed for chromosomes 13, 16, and 21. Approximately one third of fetuses with Down syndrome (trisomy 21) fetuses survive to term. All chromosome trisomies except for trisomy 1 are reported in abortuses.

Of interest, trisomy 1 is reported in embryos obtained with in vitro fertilization (IVF). This finding logically suggests that trisomy 1 is most likely lethal at the preimplantation stage.

Autosomal monosomies are rarely, if ever, observed. In contrast, monosomy X (Turner syndrome) is frequently observed, and it is the most common chromosomal abnormality observed in SABs. Turner syndrome accounts for 20-25% of cytogenetically abnormal abortuses.

Other abnormalities include those related to abnormal fertilization (eg, tetraploidy, triploidy). These abnormalities are not compatible with life. Tetraploidy occurs in approximately 8% of chromosomally abnormal abortions, resulting from failure of an early cleavage division in an otherwise normal diploid zygote.

Parental chromosomal abnormalities

Structural rearrangements occur in approximately 3% of cytogenetically abnormal abortuses. Structural chromosomal abnormalities are thought to be most commonly inherited from the mother. Of note, structural chromosomal problems found in men often to lead to low sperm concentrations, male infertility, and, therefore, a reduced likelihood of pregnancy and miscarriage. The exception to this situation is the couple undergoing assisted reproductive technologies in which selected sperm can be injected into oocytes to force fertilization by using potentially genetically abnormal sperm.

Among structural rearrangements, translocations (most commonly reciprocal and Robertsonian) can be balanced or unbalanced. The incidence of translocations increases with the number of abortions. Slightly more than one half of unbalanced rearrangements result from abnormal segregation of Robertsonian translocations. Approximately one half of all unbalanced translocations arise de novo during gametogenesis. In reciprocal translocations, children created from these gametes have normal and carrier karyotypes. Adjacent segregation results in unbalanced distribution of the chromosomes involved in the translocation, leading to partial trisomy for 1 chromosome and partial monosomy for the other chromosome. The severity of the phenotype depends on the chromosomes involved and on the positions of their breakpoints. The risk is increased if the female partner carries the translocation.

Other structural rearrangements, such as inversions or ring chromosomes, are relatively rare. These chromosomal abnormalities can be associated with congenial malformations and mental retardation, as well as SAB.

Genetic abnormalities

Certain genetic mutations thought to be involved with implantation may predispose a patient to infertility or even miscarriage. An example of a single gene disorder associated with recurrent pregnancy loss is myotonic dystrophy, an autosomal dominant neuromuscular disorder with high penetrance. The cause of the abortion is unknown, but it may be related to abnormal gene interactions combined with disordered uterine function.

Other presumed autosomal dominant disorders include lethal skeletal dysplasias (eg, thanatophoric dysplasia and type II osteogenesis imperfecta).

Maternal disease associated with increased fetal wastage includes connective tissue disorders, such as Marfan syndrome, Ehlers-Danlos syndrome, homocystinuria, and pseudoxanthoma elasticum.

Hematologic abnormalities associated with recurrent pregnancy loss include dysfibrinogenemia, factor XIII deficiency, congenital hypofibrinogenemia and afibrinogenemia, and sickle cell anemia.

Women with sickle cell anemia are at increased risk for fetal loss, possibly because of placental-bed microinfarcts.

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