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Objectives: We hypothesize that the diagnostic yield and pregnancy outcomes of patients with recurrent abortion have improved over the past 10 years., Study Design: The study was performed in an academic medical center. Diagnoses and outcomes for group A, a published series of 100 patients investigated for recurrent abortion in the section between 1968 and 1977, was compared with those for group B, the 131 patients seen between 1987 and 1991. A standardized protocol was followed, enhanced by new techniques and autoimmune investigations in the latter group. Results were compiled retrospectively. Descriptive statistics and chi 2 analysis were used., Results: No cause could be found in 37% of patients in group A compared with 24% of couples in group B (p less than 0.05). No clear difference could be shown in the subsequent outcomes of pregnancies., Conclusions: Our ability to establish a cause of recurrent abortion has improved slightly over the past 15 years. The gain is not yet reflected in successful pregnancy rates. Multicenter trials are indicated.

Probes for unique and repetitive copy deoxyribonucleic acid (DNA) are available to detect and characterize Y DNA. The probe pS4 detects repetitive copy DNA mapped to Yq12. The upper limits of the pS4 sequences are defined by the upper limits of C-banding. The probe 4B-2 is a recombinant phage construct developed from a Y library and contains a unique copy 3.3 kb Eco RI fragment mapped to Yq11. A family was ascertained through a pregnant female who had a history of four consecutive abortions and two normal daughters. Cytogenetic analysis revealed the mother and one of her daughters to have a 46,XX,15p+ karyotype. Amniocytes were karyotyped as 46,XY,15p+. Genomic DNA from controls, mother, daughters, and amniocytes was digested with Mbo I and hybridized to 32P-labeled pS4 probe. DNAs from both 46,XX,15p+ females and 46,XY,15p+ amniocytes demonstrated a clear male-specific 2.3 kb band. Digestion of the same genomic DNAs with Eco RI and blot hybridization to 32P-labeled 4B-2 probe revealed the 3.3 kb male-specific band only in the 46,XY,15p+ amniocyte DNA. The additional sequences located on 15p segregating in the female members of this family correspond to Yq12. The effect of this additional DNA on gametogenesis is unknown.

The clinical management of repetitive first-trimester pregnancy loss is handicapped by inadequate answers to four fundamental questions. These questions center around understanding the true scope of the problem, differentiating between euploidic and aneuploidic loss, identifying the parental source of the gametogenic error, and clarifying the role of molecular developmental mutants in euploidic abortion. In spite of these limitations a diagnostic and therapeutic program is outlined for couples with repetitive early abortion. Informational gaps are identified and the future role of molecular biology in clarifying some of these issues is optimistically outlined.

Balanced chromosomal translocations in parents and Müllerian abnormalities constitute defined causes of reproductive wastage. Fifty-nine couples with histories of recurrent abortion with or without fetal malformations were evaluated with cytogenetic studies and gynecography. In 44 of the couples with pure abortion histories of two or more spontaneous abortions, three (6.8%) balanced carrier parents were identified. In 11 couples with a mixed history of abortion plus fetal malformation, 3 (27.3%) had balanced translocations in one of the parents. The over-all incidence of Müllerian abnormalities in the group of 59 patients was 11.9%.

The causes of recurrent reproductive failure are diverse. Many of them are not evident in routine clinical practice and some are still unknown to sophisticated researchers in the field of reproduction. A rational clinical evaluation of the couple will identify the known causes and suggest the unknown causes. More recently the unknown causes have been further classified because of advances in cytogenetic techniques. Abortion material can now be divided into aneuploid and euploid conditions. Heteromorphic banding techniques are useful in exploring both the parental source and the mechanism responsible for recurrent aneuploidy. Delays in ovulation and fertilization may be closely linked to these cytogenetic errors. Identification of euploid abortuses in this unknown group will allow for diagnosis of endocrine, immunologic, and teratologic causes yet to be discovered. With identification of known causes, the treatment is clear cut. All other couples are at the present time dependent upon the availability of techniques to identify unknown causes. Treatment must center on normalization of ovulation, synchronization of sperm deposition and ovulation, and optimization of the maternal environment in which fertilization will occur for these couples of unknown causes.

From 1958 through 1977, 100 couples with documented recurrent reproductive failure were evaluated in the reproductive endocrine unit of the Medical College of Georgia. All couples underwent cytogenetic studies, radiologic evaluation of the Müllerian system, and timed endometrial biopsy. Recurrent pregnancy wastage was found to be associated with genetic disorders in 25 couples. Müllerian anomalies in 15, endocrine anomalies in 23, and negative findings in 37. The subsequent reproductive performance of each group is reviewed.

The evaluation of recurrent embryopathy in man is one of the most difficult tasks. The physician must clearly recognize which couples are experiencing recurrent euploidic abortion and which couples are experiencing recurrent aneuploidic abortion. A firm knowledge of the cytogenetic character of the abortion material enables one to make the next step, namely to determine the source of error in gametogenesis. Techniques are gradually becoming available to identify the source of the parental gametogenic area. In addition, new methods to detect molecular mutation in euploidic abortion are gradually evolving. The establishment of normal protein profiles by two-dimensional gel electrophoresis in normal abortions should enable one to screen recurrent embryopathy in man for abnormal proteins. Abnormal proteins, once identified, can enable us to identify the specific DNA mutation that may be at the heart of the problem.