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Cytogenetic data from the United States NICHD collaborative study of chorionic villus sampling (CVS) were used to evaluate the clinical significance of chorionic mosaicism. The 10,754 patients with normal cytogenetic results were compared with 108 patients (1.0 per cent) with placental mosaicism and 181 patients (1.6 per cent) with pseudo-mosaicism. Of the pregnancies intended to continue, the pregnancy loss rate was significantly greater in patients with placental mosaicism than in the cytogenetically normal cohort (8.6 vs. 3.4 per cent, p less than 0.05). However, there was no difference in the frequencies of abruptio placenta, preterm labour or delivery, small-for-gestational-age newborns, pregnancy-induced hypertension, or neonates with Apgar scores less than 7.

Unlabelled: Recently, we detected fra(X)(q27.3) in amniocyte cultures from female identical twins. The pregnant woman did not exhibit fra(X)(q27.3) in whole blood cultures but was the sister of 2 affected brothers. DNA marker analyses showed that she was a carrier of FRAXA. Amniotic fluid cultures (AFCs) from twins A and B exhibited the fragile X [fra(X)] chromosome, but the level of cytogenetic expression was very low in twin A's AFCs. DNA marker studies indicated both twins were carriers of FRAXA. Peripheral umbilical blood sample (PUBS) cultures exhibited fra(X)(q27.3) at a frequency of about 10% for both twins. DNA fingerprinting indicated that the twins were identical, confirming the clinical impression, with a very thin separating amniotic membrane. To our knowledge, this is the only report of prenatal fra(X)(q27.3) detection in female identical twins, and the second report of identical twin detection [Rocchi et al., 1985]. We have diagnosed prenatally fra(X)(q27.3) in 5 female fetuses using AFCs. The average fra(X) frequency was 4% for these positive female fetuses with a range of 0.5% to 8.5%. Follow-up whole blood studies confirmed our original results at an average fra(X) frequency of 25%., In Conclusion: 1. Low frequencies, perhaps 1 or 2%, or a few positive cells in AFCs, are likely to increase in magnitude when confirmed in whole blood cultures either pre- or postnatally. 2. It appears likely that the risk is low for false positive results in AFCs when low frequencies of fra(X)(q27.3) are encountered.

The acardius syndrome is a rare complication of monozygotic twin pregnancies, occurring once in 35,000 births. The outcome is invariably fatal for the acardiac twin and for 50-75% of the normal twins. We present a surgical approach to the treatment of this problem involving hysterotomy and selective delivery of the acardiac twin, which we have used in five cases. In the first case, placental abruption shortly after the procedure led to fetal death. The next two cases resulted in cesarean delivery of the remaining healthy singleton at 35 weeks' gestation. The fourth and fifth cases were delivered at 27 and 28 weeks' gestation, respectively, the first because of preterm rupture of membranes 2 weeks after the procedure and the second because of partial placental abruption 8 weeks after surgery; both of these infants are now doing well. There were no residual maternal complications. We conclude that hysterotomy has direct applicability in the management of these high-risk pregnancies.

This study demonstrates a clear and current role for multicolor in situ hybridization in expediting positional cloning studies of unknown disease genes. Nine polymorphic DNA cosmids have been mapped to eight ordered locations spanning the Charcot-Marie-Tooth type 1 (CMT1A) disease gene region in distal band 17p11.2, by multicolor in situ hybridization. When used with linkage analysis, these methods have generated a fine physical map and have firmly assigned the CMT1A gene to distal band 17p11.2. Linkage analysis with four CMT1A pedigrees mapped the CMT1A gene with respect to two flanking markers (8B10-5 cM[LOD 5.2]-CMT1A-3.5 cM[LOD 5.3]-10E4). Additional loci were physically mapped and ordered by in situ hybridization and analysis of phase-known recombinants in CMT1A pedigrees. The order determined by multicolor in situ hybridization was 17cen-LEW301-8B10-5H5/6A9-VAW409- 5G7-6G1-4A11-VAW412-10E4-pter. Two ordered probes, 4A11 and 6G1, reside on the same 440-kb partial SfiI restriction fragment. These data demonstrate the ability of in situ hybridization to resolve loci within 0.5 Mb on early-metaphase chromosomes. Multicolor in situ hybridization also excluded the possibility of pericentric inversions in two unrelated patients with CMT1 and neurofibromatosis type 1. When used with pulsed-field gel electrophoresis, multicolor in situ hybridization can establish physical location, order, and distance in closely spaced chromosome loci.

The Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy) loci have been reported to be on at least three chromosomes: 1 (CMT1B, HMSN1B), 17 (CMT1A), and X (CMTX). In this study multipoint linkage analysis of two Duffy-linked families given a combined LOD score of 8.65 to establish that the Duffy-linked CMT1B gene exists in the 18 centimorgan region between the antithrombin III gene and the Duffy/sodium-potassium ATPase loci. The simultaneous segregation of polymorphisms near the CMT1A locus on chromosome 17 excludes linkage to this chromosome region in both families. Polymorphic sites that flank the CMT1B gene have been subchromosomally localized to the proximal chromosome-1 long arm (1q21.2----1q25) by spot blot analysis of sorted chromosomes, polymorphic deletion analysis, in situ hybridization, and multipoint linkage analysis.

Immunochemical serum assays for human chorionic gonadotropin (hCG), the free ahCG subunit, and progesterone (P) were considered separately and in combination for their ability to screen for chromosomally abnormal pregnancies in the first trimester. Maternal serum was collected from 141 women undergoing chorionic villus sampling at 9-12 menstrual weeks. Trisomy 21 pregnancies had significantly higher hCG levels, while trisomy 18 and 13 pregnancies had markedly lower hCG and progesterone levels than those of chromosomally normal pregnancies. However, the discrimination of normal from aneuploid pregnancies was poor with either hCG alone, progesterone alone, or free ahCG alone. Much improved discrimination was obtained by combining hCG, free ahCG, and P into an aneuploidy index [(P/hCG)(free ahCG/hCG)]. This index distinguished 9 out of 17 (53 per cent) of the trisomy 21 pregnancies, while only misidentifying 5 out of 112 (4.5 per cent) of the normal pregnancies. The aneuploidy index thus appears promising as a first-trimester biochemical screen for aneuploid pregnancies.

Background: The finding of an elevated level of maternal serum alpha-fetoprotein during the second trimester of pregnancy may indicate that the fetus has died or is about to die. It is uncertain, however, whether the finding is associated with an increased risk of fetal death later in gestation independent of known causes of elevation, such as the presence of neural-tube defects or multiple gestation., Methods: To address this question, we performed a case-control study of 612 women whose pregnancies ended in fetal death and 2501 women who gave birth to live infants, using reports from California vital statistics for 1987. All the women had signleton pregnancies and alpha-fetoprotein screening in the second trimester., Results: Women with elevated levels of serum alpha-fetoprotein in the second trimester of pregnancy had an increased risk of fetal death, and the risk was increased until term. Women with the highest levels of serum alpha-fetoprotein--greater than or equal to 3.0 times the median value--had a very high risk of fetal death (odds ratio, 10.4; 95 percent confidence interval, 4.9 to 22.0) as compared with women who had normal levels of alpha-fetoprotein. Maternal serum alpha-fetoprotein levels that were 2.0 to 2.9 times the median were also associated with an elevated risk of fetal death (odds ratio, 2.4; 95 percent confidence interval, 1.7 to 3.4). Elevated levels of alpha-fetoprotein were especially likely to be associated with fetal death in cases in which maternal hypertension or placental infarction was also present. CONCLUSIONs. An unexplained elevated level of maternal serum alpha-fetoprotein in the second trimester of pregnancy is associated with an increased risk of subsequent fetal death, up to four to five months after alpha-fetoprotein screening.

Fluorescence in situ hybridization (FISH) with chromosome-specific probes has been applied to detection of numerical aberrations involving chromosomes 13, 18, and 21 in metaphase and interphase amniocytes. High-complexity, composite probes for chromosomes 13, 18, and 21 were used as hybridization probes for this study. These probes were constructed as chromosome-specific libraries in Bluescribe plasmids and are designated pBS-13, pBS-18, and pBS-21. Elements of these probes bind at numerous sites along the target chromosome and, when detected fluorescently, stain essentially the entire long arm of the target chromosome. The target chromosome number (i.e., the number of chromosomes of the type for which the probe was specific) was correctly determined in 20 of 20 samples in which metaphase spreads were analyzed and in 43 of 43 samples in which interphase nuclei were analyzed; all of these studies were conducted in blind fashion. These results suggest the utility of FISH with composite probes for rapid detection of numerical aberrations in metaphase and interphase amniotic cells.

This paper reports our experience with 55 fetuses identified in utero to have a cystic hygroma. The outcome of fetuses with an isolated cystic hygroma, cystic hygroma with non-immune hydrops, and cystic hygroma with multiple anomalies was evaluated. Approximately two-thirds of karyotypes were aneuploid, and a strong association of septation and aneuploidy existed. Only five cases, four of which had isolated hygromas, came to term and resulted in live births. Two of these involved small non-septated lesions which resolved in utero.

Maternal sera (MS) taken from 1396 women prior to chorionic villus sampling at 9-12 menstrual weeks were assayed for unconjugated oestriol (uE3) and alpha-fetoprotein (AFP). Median levels increased by 41 and 26 per cent per week respectively in normal pregnancies. There were 32 pregnancies with a chromosome abnormality. The median MS uE3 and AFP were 0.73 and 0.75 multiples of the median (MoM) respectively in the ten cases of Down's syndrome (DS) but not decreased in the other abnormalities. These results suggest that both uE3 and AFP may be useful in identifying DS in the first trimester. Additional prospective studies are needed to confirm these findings.

Three hundred and thirty-nine cases of multiple gestation underwent prenatal diagnosis by amniocentesis. The spontaneous abortion rate (to 28 weeks) in this group was 3.57 per cent compared with our singleton abortion rate of 0.60 per cent. The perinatal mortality rate (PMR) and prematurity rate were not different from the singletons, and compared favourably with the PMR reported in the literature for multiple gestations which did not undergo any intervention during pregnancy. This increased abortion rate following amniocentesis may only represent the increased natural loss rate in multiple gestations, and not indicate any increased risk added by the procedure.

Sera from women carrying either chromosomally normal or aneuploid fetuses in the first half of pregnancy were assayed for human chorionic gonadotropin (hCG) bioactivity in order to determine whether differences might provide the basis for a useful antenatal screen for aneuploidy. A mouse uterine weight assay was used to assess hCG bioactivity in sera from 35 patients undergoing chorionic villus sampling (12 normal pregnancies and 23 trisomic pregnancies) and in sera from 18 patients undergoing elective second-trimester abortion (12 presumed normal pregnancies, 3 trisomic pregnancies, and 3 pregnancies with neural tube defects). The hCG bioactivity to immunoactivity (B:I) ratio of normal pregnancies progressively decreased from 7.7 +/- 1.3 at 4-5 menstrual weeks, to 4.7 +/- 0.4 at 9-12 menstrual weeks, to 3.3 +/- 0.5 at 16-20 menstrual weeks. There were no significant differences in the B:I ratios between normal and aneuploid pregnancies in either the first-trimester (4.7 +/- 0.4 versus 5.2 +/- 0.3) or the second-trimester samples (3.3 +/- 0.5 versus 2.6 +/- 0.3), despite significantly greater hCG concentrations in the trisomic pregnancies. We conclude that while aneuploid pregnancies display dysfunctional regulation of hCG expression, the bioactivity of their hCG is normal and does not appear to form the basis for a useful screen for aneuploidy.

Currently, all methods of prenatal diagnosis require an invasive approach. The next step in the continuing challenge to make prenatal diagnosis more accessible is the development of a noninvasive test. The presence of fetal cells in the maternal circulation has been debated for several decades, but traditional attempts to identify the rare fetal cell within the pool of maternal cells have met with partial success at best. Today, with the aid of highly sensitive and specific techniques such as fluorescent activated cell sorting, polymerase chain reaction, and in-situ hybridization, the task of finding the "on-in-a-million" fetal cell is moving from the realm of the imagination into that of reality.

In 2 fetuses with congenital cystic adenomatoid malformation (CCAM) with hydrops, in-utero resection of the enlarged pulmonary lobe reduced mediastinal shift and allowed expansion of normal lung tissue in both cases. In case 1, the 27-week-gestation fetus died from severe hydrops after premature delivery. In case 2, fetal CCAM resection was completed at 23 weeks' gestation. At 30 weeks a girl was delivered with no evidence of pulmonary hypoplasia. Fetal surgery can now be entertained for otherwise fatal space-occupying intrathoracic lesions.

Results of testing a family for carrier status and prenatal diagnosis for Duchenne muscular dystrophy (DMD) are best explained by somatic mosaicism in the maternal grandfather. This genetic situation was identified using segregation analysis of intragenic DNA polymorphisms, a serum creatine phosphokinase assay, and physical examination of the patients. This event at the DMD locus represents one more potential source of error in carrier testing and prenatal diagnosis.

The purpose of this study was to compare patterns of self-reported mood states of women having chorionic villus sampling (CVS) (n = 151) to those of women electing amniocentesis (n = 30) with the indication of advanced maternal age. Mood states were defined as scores on the 6 subscales of the Profile of Mood States (POMS). Women at 4 U.S. prenatal diagnostic facilities completed the POMS at 4 assessment periods. These were a) at their initial genetic counseling session, b) 2 weeks post CVS results (or an equivalent time), c) 2 weeks post amniocentesis results (or an equivalent time), and d) at 30 weeks gestation. Repeated measures analysis of variance revealed that anxiety, fatigue, and confusion decreased, and vigor increased in both groups as the pregnancy progressed. Depression decreased in both groups and then increased at assessment 4 in women in the amniocentesis group but not in those electing CVS. Results should be interpreted in conjunction with obstetrically and genetically-oriented findings regarding safety and accuracy to help women decide between the 2 procedures.

Asian couples at risk for a fetus with homozygous alpha-thalassemia (hydrops fetalis) are often identified by their low erythrocyte mean corpuscular volume (MCV) and normal hemoglobin electrophoresis when little time remains to test their genotypes by restriction enzyme analysis. DNA analysis is performed directly on chorionic villi or amniocytes remaining after an aliquot is used to establish a backup cell culture. The polymerase chain reaction (PCR) protocol quickly determines whether the fetus has hydrops fetalis without waiting for cultured cells to grow. Previously, growing cultured fetal cells to obtain more fetal material to establish unambiguously the fetal genotype with two independent restriction enzyme digests absorbed a significant portion of the time remaining to complete prenatal diagnosis. A dual restriction enzyme digestion protocol was development using a 3' zeta-globin probe to clearly distinguish the most common alpha-thalassemia deletions that represent nearly all the alpha-thalassemia haplotypes in Southeast Asia.

Four cases of multiple gestation with second trimester death of one fetus and subsequent damage to a survivor are reported. Monochorionic placentation was documented in three of the cases. Central nervous system lesions occurred in all cases, and bowel injury was noted in two of the damaged fetuses. Although rare maternal clotting problems have been reported in similar situations, none was noted in any of these four cases. Prior reports have indicated that losses in the first half of gestation were of no consequence to the surviving fetuses. These four cases contradict this suggestion, and indicate that close sonographic observation of the survivors is important in any multiple gestation where on fetus has died.

Management of the fetus with bilateral hydronephrosis is controversial; ability to predict outcome and efficacy of prenatal intervention are unknown. We studied 40 fetuses referred for ultrasonography, examination of fetal urine, and possible therapy. We retrospectively assigned fetuses to a good prognosis group if fetal urine was hypotonic (sodium less than 100 mEq/L, chloride less than 90 mEq/L, osmolarity less than 210 mOsm/L) and there was no ultrasonographic evidence of dysplasia; we assigned fetuses to a poor prognosis group if even one criterion was abnormal. Survival was greater in the good prognosis group than in the poor prognosis group (81% vs 12.5%; 87% vs 30%, excluding abortions) (p less than 0.005). We then attempted to assess the efficacy of prenatal urinary decompression by comparing outcome within the good and poor prognosis groups. Survival with intervention was greater in both the good prognosis group and the poor prognosis group (89% vs 70% and 30% vs 0%). In 6 of the 8 survivors in the good prognosis group, severe oligohydramnios was reversed by decompression. We conclude the fetal urine electrolyte levels and ultrasonographic appear helpful in predicting residual fetal renal function and neonatal outcome and that prenatal decompression may prevent the development of fatal pulmonary hypoplasia.

Chorionic villus sampling has been developed as a method of first trimester prenatal diagnosis. In order to evaluate this new approach, accurate risk figures for the procedure must be obtained. This has been difficult for a number of reasons, including establishment of baseline fetal loss rates in the first trimester, procedural "learning curves," and reporting biases. This review will discuss these problems and use data from the chorionic villus sampling program at the University of California, San Francisco, to illustrate difficulties in data interpretation.

Cervical cystic hygroma is thought by most pediatric surgeons to be an isolated, usually resectable lesion with an excellent prognosis. However, prenatal sonography has revealed a high "hidden mortality" among fetuses with this condition, and most perinatologists consider it to be uniformly fatal. In an attempt to resolve these two differing perspectives, we analyzed 29 cases seen at two centers over 4 years. Of 27 fetuses diagnosed before 30 weeks' gestation, only one survived. Twenty-five of the 27 were aborted; severe hydrops was present in 21 of these 25. Two of the 27, both with stigmata of Noonan's syndrome, underwent spontaneous regression during the second trimester: one died at 2 weeks of age, and the other survived. Successful karyotypes were obtained on 17 fetuses: nine were normal, seven were 45X, and one was trisomy 21. Fetuses with abnormal karyotypes had a lower incidence of polyhydramnios (0% v 67%), additional anomalies (12% v 67%), and consanguinity or a history of abnormal pregnancies (0% v 89%). Two fetuses were diagnosed after 30 weeks' gestation. Neither had hydrops, polyhydramnios, associated anomalies, or an abnormal karyotype. One had a completely normal sonogram at 17 weeks' gestation. Both were operated on within the first 4 days of life; one did well without complications, and the other required a permanent tracheostomy because of extensive hypopharyngeal involvement. A cystic hygroma presenting in the fetus has a different natural history and prognosis from one presenting postnatally. The vast majority of fetal cases are diagnosed before 30 weeks' gestation, and present with hydrops or diffuse lymphangiomatosis. The dismal outlook in this group justifies elective termination in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Sonograms of fetuses at risk for congenital lethal osteogenesis imperfecta (osteogenesis imperfecta type II) were retrospectively reviewed blindly and correlated with pregnancy outcomes. Six of eight cases of type II osteogenesis imperfecta were correctly diagnosed with use of the proposed criteria of multiple fractures, demineralization of the calvaria, and femoral length more than 3 standard deviations below the mean for gestational age. The two cases not diagnosed had sonographic abnormalities but did not meet all three criteria. Among 18 pregnancies genetically at risk for the disease but with normal outcomes, all sonograms were normal, meeting none of the proposed criteria. Among an additional 25 fetuses with osteochondrodysplasias, no case satisfied all three of the proposed diagnostic criteria. With use of strict standards for the diagnosis of type II osteogenesis imperfecta, this disease can be distinguished from other fetal skeletal abnormalities. In a pregnancy at risk for recurrence of osteogenesis imperfecta, a normal sonogram after 17 weeks excludes this lethal condition.

Review of our experience with 45 cases of prenatally diagnosed congenital diaphragmatic hernia (CDH) confirms that most fetuses (77%) will not survive despite optimal pre- and postnatal care. Polyhydramnios, associated anomalies, early diagnosis, and a large volume of herniated viscera (including liver) are associated with a particularly dismal prognosis. After extensive experimental work demonstrated the efficacy, feasibility, and safety of repair in utero, we attempted to salvage six highly selected fetuses with severe CDH by open fetal surgery. Five had liver incarcerated in the chest: three died at operation because attempts to reduce the liver compromised umbilical venous return. In one, a Goretex diaphragm was constructed around the liver, but the baby died after birth. The last two fetuses, one with incarcerated liver, were successfully repaired. Both demonstrated rapid growth of the lung in utero, had surprisingly good lung function after birth despite prematurity, had the abdominal patch removed at 2 weeks, and subsequently died of nonpulmonary problems (an unrelated nursery accident in one and intestinal complications in the other). The only maternal complication was amniotic fluid leak and preterm labor. All six women are well and four have had subsequent normal children. From this phase I experience, we conclude that fetal surgery appears safe for the mother and her reproductive potential, that fetal CDH repair is feasible in selected cases, and that the fetal lung responds quickly after decompression. However, fetal repair remains a formidable technical challenge.

Using monoclonal antibodies and indirect immunofluorescence an easy, reliable, inexpensive micromethod for the quantitative analysis of fetal lymphocyte markers was developed. Monoclonal antibodies specific for identification of all peripheral T lymphocytes (OKT 3), the subclass of suppressor/cytotoxic T lymphocytes (OKT 8), and for B lymphocytes (OKla 1) were employed. This technique will permit in utero recognition of immunodeficiency states which alter the ratio of these cell types.

The antenatal diagnosis of abdominal wall defects has allowed improved perinatal management. For fetuses with associated anomalies, the options of elective termination or minimal intervention can be offered. Our ability to predict the extent of bowel damage in gastroschisis based on the ultrasound findings enables us to offer early delivery to those fetuses who are at high risk. The data are not clear at the present time whether cesarean section offers any advantage. These fetuses should, however, be delivered at a center which is capable of providing high level medical and surgical care to these potentially ill infants. Initial resuscitation of these neonates requires early insertion of an intravenous line and a nasogastric tube, the administration of antibiotics, sterile coverage of the eviscerated bowel, and careful attention to temperature instability. Neonates with gastroschisis should be operated on as soon as they are stable, whereas infants with omphalocele can be investigated for associated anomalies prior to surgery. Primary fascial closure is performed whenever possible. Where this is not possible, a staged repair using a silastic chimney achieves closure within 3-6 days. Skin coverage alone or nonoperative management is reserved for the few cases with giant omphalocele, associated anomalies, or poor operative risk. Decisions about primary versus delayed closure, while usually dictated by clinical judgement, can be aided by indirect measurement of intraabdominal pressure. Postoperative ventilation, and consideration of long-term nutritional needs, are also important parts of the perioperative management.

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.

Seven infants have been studied who have a similar pattern of severe craniofacial and limb anomalies associated with aberrant tissue bands. The craniofacial anomalies consist of unusual encephaloceles, facial clefts, and cranial plus midfacial distortion; the limb anomalies consist of constrictions, amputations, and pseudosyndactyly. These defects are interpreted as being secondary to the early distorting and disruptive effects of aberrant tissue bands, the etiology for which is undetermined. Survival beyond the neonatal period has occurred in four of the five liveborn patients, indicating that early death should not necessarily be anticipated. Recurrence risk is apparently negligible.

Sonographically directed placental aspiration has been investigated as a method for obtaining fetal erythrocytes. The technique is generally successful and the fetal red cells are generally usuable for the prenatal diagnosis of the hemoglobinopathies.

Our custom dual laser chromosome sorter has been used to characterize and isolate metaphase human chromosomes rapidly for gene mapping purposes. Herein, we tested how well this system could detect unknown abnormal human chromosome constitutions. These results were compared to those of conventional cytogenetic analyses by banding and photomicrography. The sorter was used to analyze each cell line stained with two different stain pairs: DIPI-chromomycin and Hoechst-chromomycin. In 20 min, two histograms representing 2 X 10(5) chromosomes each were collected for each stain pair. A blind study of 11 samples by flow analysis demonstrated excellent concordance between the abnormal chromosomes detected and the diagnoses of Giemsa-banded karyotypes. Aneuploidy was identified by changes in the number of chromosomes in each histogram peak, while rearrangements such as deletions and translocations caused shifts in the histogram peak positions. The direction and distance of histogram peak shifts are directly related to alterations in chromosome size and banding pattern. We conclude that dual-laser flow analysis may provide a rapid approach to the screening and diagnosis of chromosome abnormalities.

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.

Prenatal diagnosis of disorders of galactose metabolism was done in one instance in a family with a known galactokinase deficiency and in six cases in five families at risk for galactosemia. The galactokinase activity in cultured amniotic cells was found to be normal, and the diagnosis was confirmed postnatally. In the six pregnancies at risk for galactosemia, four were considered to be unaffected and two to be affected. Of the latter, one was carried to term, and the erythrocyte transferase activity of the baby was shown to be absent. The other pregnancy was terminated, and examination of fetal tissues by biochemical studies confirmed the diagnosis. This experience substantiates the concept that prenatal diagnosis of disorders of galactose metabolism is feasible.

Prenatal diagnosis by amniocentesis in the second trimester of pregnancy has become widely accepted, and the demand for the procedure is increasing exponentially. It is important to reevaluate critically the time and effort spent obtaining a detailed pedigree analysis and family history prior to amniocentesis. Two hundred unselected consecutive cases of women undergoing amniocentesis because of advanced maternal age were studied. One woman had a brother with Duchenne muscular dystrophy and she was found by CPK testing to be a carrier. The prenatal diagnosis revealed that she was carrying a male fetus with a 50% chance of being affected, and the couple decided to have a termination of the pregnancy. A variety of other familial disorders and teratogenic exposures which were found in the studied 200 families were further explored through genetic counseling. Additional reasons for the individual pre-amniocentesis counseling include reducing anxiety and responding to specific psychosocial aspects of the prenatal diagnosis procedure in particular families.

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.

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.