Frederick C. Koppitch

Genetic diagnosis in the first trimester: The norm for the 1990s

Increasing technical capabilities and patient motivation for earlier and more private prenatal genetic diagnosis have allowed us to alter the concept of first-trimester genetic diagnosis from being rare to routine in our tertiary Reproductive Genetics Center. As public awareness of available services has increased, we have seen steadily increasing numbers and proportion of patients who are referred by their physicians earlier, who schedule tests earlier, opting to have earlier testing, and accept slightly higher risks in return for earlier results and privacy. Analysis of our clinical and laboratory results and complication rates suggests that first-trimester genetic diagnosis by either chorionic villus sampling or early amniocentesis may be offered to virtually all patients who would be candidates in the midtrimester. We believe that this trend will accelerate, making first-trimester diagnosis the norm, rather than the exception, for the 1990s.

Postmortem chorionic villus sampling is a better method for cytogenetic evaluation of early fetal loss than culture of abortus material

In utero chorionic villus sampling at the time of diagnosis of intrauterine fetal death is compared with more traditional use of cultured fetal skin, products of conception, or amniocentesis. A total of 102 specimens from early fetal losses were evaluated for success in karyotyping and chromosomal results. We found postmortem chorionic villus sampling is technically possible, offers the highest likelihood of getting a cytogenetic result, and is a rapid, reliable, and safe technique. The extraembryonic component of intrauterine fetal deaths appears to remain viable and continues to grow long after the embryo has died. Samples obtained at the time of diagnosis of fetal death offer the greatest changes of successfully obtaining a karyotype. The incidence of chromosome abnormalities associated with fetal loss, particularly trisomies, is higher than previous data suggested.

Viable Pregnancies after Diagnosis of Trisomy 16 by CVS: Lethal Aneuploidy Compartmentalized to the Trophoblast

Increasing utilization of chorionic villus sampling (CVS) has lead to the discovery that the placenta can karyotypically be a very heterogeneous organ, and chromosomal mosaicism within the placental can confuse cytogenetic interpretation. Recently, confined placental mosaicism (confined regions of aneuploidy in the otherwise normal diploid placental and fetus) has been described involving a number of chromosomal abnormalities. Fetal trisomy 16 is considered uniformly lethal early in gestation. However, we present 3 cases of nonmosaic trisomy 16 confined regionally to the placenta. We discuss the possible etiology, impact on the developing fetus, and suggest an approach to the workup and evaluation of cases where the karyotype obtained on CVS is not compatible with the findings on ultrasound.

Establishment of a collaborative university-commercial maternal serum α-fetoprotein screening program: A model for tertiary center outreach

Expansion of the availability of tertiary level services beyond major medical centers has proved to be a major problem in health care delivery. Routine maternal serum alpha-fetoprotein screening for neural tube defects, and now also for aneuploidy, is a classic example in which there has been a schism between the clinical expertise to manage such a program within a tertiary level reproductive genetics center and the ability to reach patients in regions that are not routinely accessible to the tertiary center. To address this problem we have established a collaborative university-commercial laboratory statewide maternal serum alpha-fetoprotein program that we believe can serve as a model for others. In the first 4 months since its implementation, the program volume has increased tenfold. The detection frequency of neural tube defects has been consistent with that of other programs (1/1690). Three aneuploid karyotypes were found in amniotic fluid of 118 women less than 30 years old who underwent genetic amniocentesis because of a low maternal serum alpha-fetoprotein value. Thus we conclude that: the establishment of a joint university-commercial maternal serum alpha-fetoprotein program may provide a successful model for efficient tertiary center outreach, assessment of our data suggests that a population at high risk for abnormal fetuses can be identified among patients not generally considered at high risk, low maternal serum alpha-fetoprotein values may likely be a more important public health measure than high ones.

Amniotic Fluid Alpha-Fetoprotein Levels in the Differential Diagnosis of Cystic Hygroma

In 7 second trimester pregnancies ultrasound (US) demonstrated cystic hygroma colli (CHC); amniocentesis was performed in 6 patients. In the 7th patient, because of oligohydramnios, the fluid for karyotype was aspirated from the CHC. Five pregnancies had been referred secondary to abnormalities on US and 2 others because of low maternal serum alpha-fetoprotein (MSAFP). Four karyotypes were abnormal (45,X;47,XX+21; 47,XY+21; 46,XX/45,X), and 3 had normal karyotypes. Amniotic fluid alpha-fetoprotein (AFAFP) was normal in 4 pregnancies and low in 2 (0.09 MOM, 0.41 MOM). Of 2 pregnancies with trisomy 21 one had been referred for low MSAFP. In 2 pregnancies with normal karyotypes, US findings at early gestational age (14-17 weeks) of small, nonseptated, bilateral CHC disappeared during pregnancy; these women delivered normal, term babies. Most prenatally diagnosed CHC are not in fetuses with Turner syndrome. With a normal karyotype and CHC as the only finding on early US in utero, normal neonatal survival is possible. AFAFP is not elevated in pregnancies with CHC. If AFAFP is elevated with a positive acetylcholinesterase, such results may suggest that the CHC was inadvertently aspirated.

Does the Color of Amniotic Fluid Still Matter

Second trimester amniotic fluid (AF) is generally clear or very light yellow. We examined the color of 2,141 AF samples. Fifty-six specimens were brown, 35 were green. There were 71 samples with abnormal karyotype (3.46%). In the group with brown AF, there were 7 abnormal karyotypes out of 56 (12.5%). There was 1 case of aneuploidy out of the 35 green samples (2.86%). We conclude that green AF in the second trimester, absent any other findings, carries no special significance, but brown AF carries a fourfold increased incidence of chromosomal aneuploidy in patients undergoing genetic amniocentesis.

Maintenance of a Genetic Data Set on Multiple Data Base and Statistical Analysis Systems

A data base centered on chromosome analysis of amniotic cells is maintained on multiple data base management and statistical analysis systems. The data are collected from patients referred for karyotyping and genetic counseling either to the Wayne State University’s C. S. Mott Center or Detroit’s Hutzel Hospital. Data include primary and secondary McKusick and Birth Defects diagnoses, alpha-feto protein values, karyotypes, medical data from patient charts - e.g., pedigree, parity, gravidity, gestational age, past medical problems, demographic variables, such as age, address, phone, referral source, and follow-up information. The powerful interactive capabilities of the Michigan Terminal System (MTS) (l), the major operating system on Wayne State University’s Amdahl 470V/6 computer, are used for initial data entry. With the aid