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Human sperm chromosome complements were examined to assess the possibility that the conceptions of two children with the same chromosomal defect, del(13)(q22q32), from chromosomally normal parents were the result of a paternal germ cell mosaicism. Analysis of 216 complements, both by quinacrine banding and by measuring the relative length of chromosome 13, showed no unusual subpopulation of 13s; this decreased the likelihood of a paternal origin of the deletion. Sperm chromosomal analysis is a useful adjunct to available techniques in clinical genetics. When counseling cases involving either structural or numerical de novo chromosome abnormality, it is of importance to discuss the possibility of germ cell line mosaicism as well as to offer prenatal diagnosis for subsequent pregnancies.

Interest in correcting fetal pathology before birth has been stimulated by advancing experimental technology and improvements in the ability of ultrasound to look into the uterus. In this article, diagnosis, management and treatments of three congenital defects, hydronephrosis, ventriculomegaly, and diaphragmatic hernia are discussed. The future of fetal in utero surgery also is considered.

We have reviewed the current status of prenatal diagnosis for chromosomal indications and for neural tube defects. The number of pregnancies monitored will increase as greater resources become available and as public education about genetics increases. The methodology has proved to be a powerful means of preventing the birth of individuals with significant genetic defects, thereby sparing both parents and society from the burdens produced by such disorders. In the future, it is likely to be even more effective.

Recent advances in techniques for fetal catheterization and surgical manipulation have made intrauterine therapy of certain anomalies a reality [1 -4]. With a variety of treatment options now available, the fetus must be afforded as cornprehensive a diagnostic evaluation as possible. It may be insufficient to identify an abnormality and await delivery to perform a more complete diagnostic workup. Precise and detailed anatomic information is necessary to select appropriate cases for prenatal therapy and to plan the most efficacious therapeutic approach. We recently encountered a fetus with urinary tract obstruction in whom combined radiologic and sonographic imaging was necessary to establish the level of obstruction.

Chromosomal abnormalities were studied in 33,551 abortions and births to women whose contraceptive histories had been recorded at their first antenatal visit in 1975–1977. Chromosome examinations were performed exclusively on clinical grounds. There were 45 de novo abnormalities detected (1.34/1,000); three of them were detected at amniocentesis. Trisomy 21 was observed in 27 cases (0.80/1,000), trisomy 18 in nine (0.27), other trisomies in three (0.09), and translocations or deletions in five (0.15). One case of triploidy and six cases of inherited abnormalities were detected. There were no significant racial variations. No increase in risk for chromosomal abnormalities was found among women who had used oral contraceptives prior to becoming pregnant or among women who experienced oral contraceptive breakthrough pregnancies. Two cases of trisomy 18 were observed among the 814 deliveries following oral contraceptive breakthrough conceptions (2.46/1,000), two cases of trisomy 21 occurred in 338 births following failures of rhythm contraception (5.92/1,000), and no cases of trisomy 21 or 18 among the 1,569 women using spermicides at the time of conception.

Chorionic villus sampling (CVS) has emerged as a first trimester alternative to amniocentesis for the prenatal detection of genetic disorders. We report our experience in 600 consecutive CVS procedures to better delineate the safety, efficacy and reliability of this new method of prenatal diagnosis. Adequate samples were obtained at the initial visit in 97 per cent of the cases, and successful cultures were established in 98.7 per cent of these patients. Chromosome abnormalities were detected in 5.9 percent of those pregnancies tested because of advanced maternal age (greater than or equal to 35 years). A discrepancy between the villus karyotype and that of the fetus was found in 2.0 per cent of cases, and most commonly consisted of mosaicism in the villus sample for a chromosomal abnormality that was not found in fetal samples. The risk of spontaneous abortion following the procedure was 6.3 per cent. We conclude that chorionic villus sampling is an acceptably safe and reliable procedure, but further investigation is needed before it can become an established technique in prenatal diagnosis.

From 1973 to 1983, cytogenetic analyses were performed on blood samples from 144 couples referred because of two or more spontaneous abortions. Any couple with abnormal offspring in addition to the miscarriages was excluded from the study. Two balanced translocations were found in the 288 individuals examined (0.7%). There was a high frequency of phenotypically normal individuals with cells hyperploid for the X chromosome. This may be a manifestation of an impaired genetic control of chromosome disjunction in these patients.

A fragile site (q27) of the X chromosome has been associated with X-linked mental retardation, and the prenatal diagnosis of the fragile (X) syndrome has been shown to be possible. It is suggested that both fluorodeoxyuridine and methotrexate in thymidine-deficient media be used to demonstrate the fragile (X) in cultured amniotic fluid cells. The fetus diagnosed in utero demonstrated the dolichocephaly, large ears, flattened malar area, and large testes characteristic of the fragile (X) syndrome in the newborn period.

During the period from 1978 to 1983, 92 pregnancies have been evaluated by fetoscopy for the prenatal diagnosis of hemophilia A. Satisfactory fetal plasma samples were obtained in 80 instances and the diagnosis--or exclusion--of hemophilia was made by immunoradiometric assay of the factor VIII coagulant protein (VIII:CAg). The accuracy of the diagnosis established by fetoscopy has been verified after delivery or termination, and there have been no misdiagnoses resulting from laboratory error. Additional evidence for the accuracy of the analysis was the observation that the frequency of hemophilia in pregnancies of obligate carriers of the hemophilia gene, and of women whose plasma assays were indicative of the carrier state, was 29 of 59 fetuses at risk. In one case of cross-reacting material-positive hemophilia, samples obtained at fetoscopy and from the newborn infant had normal VIII:CAg levels but the infant had decreased factor VIII procoagulant activity. There were five fetal deaths resulting from fetoscopy in 55 pregnancies not intentionally terminated. Although only a small percentage of pregnant hemophilia carriers in the United States have elected to undergo fetoscopy for prenatal diagnosis, this procedure has allowed a number of pregnancies to go to term with delivery of normal males in families that were not willing to accept the risk of a hemophilic child. In eight instances, fetoscopic evaluation was sought for two successive pregnancies.

Forty-four fetuses were studied sonographically because of an elevated amniotic fluid alpha-fetoprotein level noted during routine amniocentesis, questionable findings during an ultrasound examination at another institution, or a history of a neural tube defect in prior pregnancy. Eleven neural tube defects, 16 non-neural tube defect anomalies, and 17 normal fetuses were all correctly identified by sonography. Ultrasound answers the need for a second diagnostic tool to complement the alpha-fetoprotein measurement.

Prenatal diagnosis of beta-thalassaemia and sickle-cell anaemia was attempted in 24 pregnancies. Adequate amounts of fetal blood (for studying globin-chain synthesis) were obtained in 22 cases. 4 cases of homozygous beta-thalassaemia and 2 of sickle-cell anaemia were diagnosed. The difference between the homozygous and non-homozygous states was well defined. Fetal bleeding from cord puncture and amnionitis resulted in the loss of three fetuses, and methods to avoid these complications are being devised. It is concluded that prenatal diagnosis of disorders of beta-globin synthesis is feasible.

This paper describes the application of bivariate flow karyotyping to (1) classification of chromosomes isolated from cultures of cells taken by amniocentesis and (2) detection of numerical and structural aberrations. Chromosomes were isolated from primary cultures 2-5 wk after amniocentesis, stained with Hoechst 33258 and chromomycin A3, and analyzed using dual beam flow cytometry. Information about chromosome DNA content and DNA base composition was derived from the locations of the peaks in the flow karyotypes, each peak being produced by one or more chromosome types with similar DNA content and DNA base composition. Information about the relative frequency of each chromosome type was determined on the basis of the relative volume of the peak for that chromosome type. Cytogenetic information determined on the basis of flow karyotypes was compared with that obtained by visual analysis following G-banding. Variability among the peak means and volumes in flow karyotypes was determined from analyses of 50 normal amniocyte cultures. Numerical aberrations involving chromosomes 21, 18, and Y were detected correctly in all of 28 analyses, including eight in a blind study. Structural aberrations involving chromosomes 1, 2, 3, 6, 9-12, 13, 14, 15, 21, and 22 were detected in all of seven cultures in a blind study. Flow karyotypes proved to be insensitive to small, normally occurring chromosome polymorphisms detected by banding analysis. In addition, a few samples were erroneously scored as having numerical aberrations.

By comparing fetal femur length to biparietal diameter a fetus at risk for osteogenesis imperfecta type II was diagnosed in the early second trimester of pregnancy. Real-time ultrasound is a reliable non-invasive technique for the prenatal diagnosis of fetal dwarfism syndromes.

Anxiety was measured and compared in three groups of 12 pregnant couples undergoing amniocentesis for prenatal diagnosis of chromosomal disorders. Significant elevations in anxiety were found in all groups prior to counseling on the day of the procedure and prior to receiving test results. Women who had previously given birth to a child with a chromosomal disorder displayed higher anxiety levels prior to amniocentesis than women whose indication for the procedure was age. Fathers in the previous trisomy group had higher anxiety levels prior to the receipt of test results as well as before the amniocentesis when compared to fathers in the maternal-age group. An experimental group of couples in which the women were over 35, received weekly calls from the genetic counselor. This intervention did not reduce median anxiety scores significantly for either men or women but did lower anxiety among the minority of extremely anxious mothers. Parental anxiety levels were interpreted based on interview data. Conditions which promote anxiety were contrasted to those which diminish it. Suggestions were made for amniocentesis counseling earlier in pregnancy and for identifying parents who would benefit by extra attention from counselors.

The development of fetoscopy and the ability to obtain fetal blood samples have made possible the prenatal diagnosis of diseases not diagnosable by amniocentesis. Foremost among these disorders are the hemoglobinopathies. We report our experience in establishing the first program for fetoscopy and fetal blood sampling in the Middle East. The results demonstrate that the experience and training required for a fetoscopy and fetal blood sampling program can be obtained in about one year. During that year, 23 couples who fetuses were at risk for a hemoglobinopathy learned the genetic status of their fetuses.

ALTHOUGH many fetal anatomic abnormalities can now be diagnosed by sonography, only a few will affect prenatal management.1 In the fetus with severe bilateral hydronephrosis secondary to urethral o...

Perinatal obstetricians, surgeons, ultrasonographers, pediatricians, bioethicists, and physiologists from centers active in fetal treatment (13 centers in 5 countries) gathered at Santa Ynez Valley...

Reported survival rates in nonimmune hydrops fetalis vary considerably. Among 27 fetuses exhibiting severe sonographic features of nonimmune hydrops fetalis, 33% survived the neonatal period. For five of the nine survivors, the prognosis remains uncertain or poor. On the basis of sonographic features alone neither prognosis nor potential survivors were reliably predicted.

Von den mehr als 400 bekannten angeborenen Stoffwechselleiden [39] sind inzwischen bei mehr als 200 die spezifischen Enzymdefizienzen bekannt [20]. Insbesondere durch die Kultivierung von Fibroblasten und den Einsatz verschiedener biochemischer, immunologischer und gentechnologischer Techniken konnen mehr als 150 autosomal-rezessiv bzw. x-chromosomal vererbte Stoffwechselerkrankungen sicher diagnostiziert werden. Etwa die Halfte dieser Erbleiden sind aus Amnion- bzw. Chorionzellmaterial bereits pranatal diagnostizierbar [4]. Fur die meisten der in der Regel zwar mit dem Leben zu vereinbaren, aber in ihren Auswirkungen auf das Leben betroffener Kinder, v. a. durch die hochstgradige geistige Retardierung, sehr schwerwiegenden Stoffwechselleiden steht bisher keine effektive Therapiemoglichkeit zur Verfugung [6]. Eine pranatale Diagnostik war allerdings in solchen Stoffwechselleiden nicht moglich, deren Enzymdefekt nicht in Amnion- bzw. Chorionzellen oder indirekt durch DNA-Untersuchungen nachweisbar ist. Dies gilt z. B. fur die Phenylketonurie (PKU) und die Ornithintranscarbamylasedefizienz (OTC), obwohl in einem Teil dieser Falle durch Fortschritte auf dem Gebiet der Gentechnologie ein direkter Nachweis aus der DNA ohne spezifische Enzymuntersuchungen von Lebergewebsmaterial moglich wird [17, 24].

A mild, short, depressive and guilt ridden period following abortion is quite common, but a severe psychological reaction is rare. The indication for the abortion and the preabortal psychological state of the patient are the two most important factors. Almost all reported instances of postabortion psychoses have occurred in patients who had severe preabortal psychiatric problems. Women undergoing abortion for socioeconomic or psychosocial indications appear to be at minimal risk for long-term negative psychological sequelae. In contrast, women in whom abortion is carried out because of exposure to rubella and the risk of fetal malformation, maternal organic disease or the prenatal diagnosis of a genetically defective fetus are at greater risk and may need supportive psychotherapy.

From June 1978 to December 1983, 100 patients with viable pregnancies involving opaque, discolored, second-trimester amniotic fluid were identified. During this period 7018 genetic amniocenteses were performed for an incidence of discolored fluid of 1.4%. Compared with case matched control subjects there were no statistically significant differences in the incidence of elevated amniotic fluid alpha-fetoprotein, preterm labor, fetal distress during labor, intrauterine growth retardation, or stillbirth. The rate of spontaneous abortion (7 versus 0%; P less than .05) was increased in the discolored fluid group. The patients with discolored fluid also had an increased incidence of prior vaginal bleeding (P less than .001).

The natural history of in utero ventriculomegaly was defined by a retrospective review of the outcome of 47 fetuses evaluated during a 5-year period by the Fetal Treatment Program at the University of California. In 20 fetuses, a diagnosis of ventriculomegaly associated with other severe abnormalities was made early in pregnancy. Termination of pregnancy was elected in 19 of 20 cases, and no fetus survived. In five fetuses, the diagnosis was made late in pregnancy and was associated with severe abnormalities. Fetuses were handled in a routine obstetric fashion and none survived. Of the other 22 fetuses 19 had stable and two had progressive ventriculomegaly; in one case, ventriculomegaly resolved in utero. Nineteen of these fetuses have survived, 13 with normal intellectual development and six with moderately to severely delayed development. Associated abnormalities were detected with ultrasonography in 74% of fetuses; there was a 20% false-negative rate of detection. Ventriculomegaly was isolated and progressive in two fetuses. In both cases, fetuses were delivered at term, and postnatally a shunting procedure was performed. Both children are neurologically normal. From our results and a review of the literature, which supports our findings, we were unable to define a group of fetuses with in utero ventriculomegaly that would benefit from in utero shunting.

Nonimmune hydrops fetalis may be associated with an elevated amniotic fluid delta OD450. Cases of I-cell disease (mucolipidosis II), lethal multiple pterygium syndrome, and alpha-thalassemia are presented, each associated with nonimmune hydrops fetalis and an elevated delta OD450. An elevated delta OD450 does not always indicate isoimmunization, and may be due to increased red blood cell turnover for a variety of reasons associated with nonimmune hydrops fetalis.

In an attempt to predict histologic fetal renal dysplasia among fetuses with obstructive uropathy, three antenatal sonographic features (presence of renal cortical cysts, echogenicity of renal parenchyma, and degree of hydronephrosis) were studied. Identification of renal cortical cysts in the kidneys of fetuses with obstructive uropathy enabled accurate prediction of renal dysplasia. Of 49 fetal kidneys with obstructive uropathy, all 15 kidneys with sonographically visible cortical cysts had severe but not necessarily lethal dysplasia (accuracy of positive prediction = 100%). Of 15 obstructed but nondysplastic fetal kidneys, none had sonographically visible cysts (specificity = 100%). The absence of fetal renal cysts on antenatal sonography, however, did not exclude the presence of dysplasia. Assessment of the echogenicity of renal parenchyma and the degree of hydronephrosis are of only limited value in predicting whether an obstructed fetal kidney will show histologic dysplasia.

In two pregnancies at risk for homozygous beta+ and beta0 thalassaemia, fetal blood mixed with maternal blood was obtained by placental aspiration and was purified to over 90% purity by differential agglutination with anti-i antibodies. Study of globulin-chain synthesis showed absence of beta-globulin chain in both fetuses. The diagnosis of homozygous beta-thalassaemia was made and was confirmed after the pregnancies were terminated. Thus, the defect in beta-globulin-chain synthesis in homozygous beta-thalassaemia is expressed in utero, and prenatal diagnosis is possible.

Studies have shown an increased incidence of chromosome abnormalities in babies of women who have taken oral contraceptives (OC) at the time of conception. The Kaiser-Permanente Birth Defects Study between 1975-1977 observed 814 babies of OC users at time of conception and found 1 case of trisomy 21 and 2 cases of trisomy 18. The frequency rate for the 3 cases of de-novo chromosome abnormality in the pill failure group was 3.69/1000 and 1.28/1000 among 32737 in the control group.

• Surgical advice is often sought when a prenatal diagnosis of gastrointestinal tract obstruction is made. We reviewed our experience with 17 such cases during a 4-year period. Eight fetuses had complete proximal obstruction. Seven of the 8 did well after maternal transport to a perinatal center and prompt neonatal surgery. Six fetuses had distal obstruction with dilated bowel and increased peristalsis. Two died after birth (1 with severe associated anomalies and 1 with short-bowel syndrome), and the other 4 did well. Three fetuses had a false-positive diagnosis of in utero meconium peritonitis. Two died and the other had no postnatal evidence of obstruction. Our data suggest (1) polyhydramnios may not be present early in gestation or with distal obstruction; (2) other anomalies, including a family history of cystic fibrosis, should be sought; (3) dilated bowel with increased peristalsis is diagnostic of fetal gastrointestinal tract obstruction, whereas intra-abdominal calcification and ascites are nonspecific findings; (4) late development of ascites in a fetus with documented obstruction may be an indication for early delivery; and (5) prenatal diagnosis permits appropriate counseling, planned delivery, and prompt postnatal resuscitation and surgery with a good prognosis in most cases. (Arch Surg. 1989;124:1183-1187)