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We describe a series of 100 cases of prenatal genetic diagnosis using the technique of chorion villus sampling. The advantage of chorion villus sampling in terms of earlier diagnosis, and its disadvantage of a higher incidence of false results, compared with amniocentesis, are noted. The comparative risks for pregnancy loss are discussed.
Chromosomal anomalies and mendelian diseases are more frequent in multiple gestations than in singletons. Prenatal diagnosis is recommended in multiple pregnancies whenever indicated. Invasive testing using amniocentesis or chorionic villus sampling can be performed safely. Chorionic villus sampling has a significant advantage over amniocentesis because it offers rapid karyotyping and biochemical and DNA studies at an early stage of pregnancy. Only experienced centers should perform these procedures because of the technical aspects and the expertise needed in handling discordant results.
Thanatophoric dysplasia is the most common type of lethal skeletal dysplasia. It can usually be diagnosed with ultrasound, but differential diagnosis with other osteochondrodysplasias is not always possible. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been demonstrated to cause two distinct subtypes of the disorder. We describe a case of thanatophoric dysplasia type I diagnosed at 18 weeks of gestation by ultrasonography. Genomic DNA obtained by chorionic villus sampling showed a C to G substitution at position 746 in the FGFR3 gene, resulting in a Ser249Cys substitution already known to be associated with type I disease. Implications for perinatal management are discussed.
A possible association of limb reduction defects with chorionic villus sampling (CVS) may be related to compromised umbilical blood flow from the trauma of the procedure. We hypothesized that because CVS may disrupt or compromise umbilical blood flow to the fetus, either by vasoconstriction, bradycardia, or emboli, we would detect these changes using Doppler velocimetry. A cohort of 21 consecutive consenting patients undergoing first-trimester elective CVS for prenatal diagnosis were entered into a prospective longitudinal study. Colour flow Doppler velocimetry was performed on fetal umbilical arterial blood flow immediately before and after CVS to measure the pulsatility index, fetal heart rate, per cent flow time, and maximum flow velocity. Measurements were obtained from three consecutive cardiac cycles in three different umbilical segments and averaged. Potentially confounding variables also recorded included gestational age, method of CVS, number of passes, number of aspirations, placental location, tissue sample size, and operator. Umbilical velocimetry values before and after CVS were compared using the paired t-test and showed no statistically significant differences. No differences were found when data were analysed by gestational age, sample size, method, number of aspirations, placental location, or operator. We were unable to detect any significant change in fetal umbilical arterial blood flow velocimetry or heart rate after performing CVS. Umbilical blood flow does not appear to be routinely compromised by CVS.
Previous reports have suggested that the fetal loss rate with transcervical chorionic villus sampling was high in the initial 100-300 procedures performed. In a consecutive series of 155 patients with first-trimester transabdominal chorionic villus sampling (CVS), we observed a total fetal loss rate of 8.4%, and loss rate not attributable to induced abortion or cytogenetic abnormality of 3.2%. Our results demonstrate that transabdominal CVS in the first trimester of pregnancy is a safe method of prenatal diagnosis.
A new operating hysteroscopic fiberscope consisting of soft and rigid parts (4.8mm outer diameter) was developed with the support of Fuji Photo Optical Company. The working part of the scope can be divided into three sections: A flexible soft front section, a rotary rigid middle section and a flexible self retained semirigid rear section. With these functional parts the intrauterine target can be approached directly to perform the following operations. 1. Directed intrauterine biopsy. Thirty-five patients diagnosed as having endometrial polyp (13), submucous myoma (8), endometrial hyperplasia (4), endocervical polyp (3), endometrial carcinoma (2) and others (5) underwent direct biopsy with hysteroscopic control. No cervical dilatation or anesthesia was necessary. 2. Transcervical recanalization. In six cases of proximal tubal occlusion, a ureteral catheter or a percutaneous coronary balloon angiocatheter was introduced into the tubal ostium of the obstructed side to resolve the occlusion successfully with concomitant laparoscopy. 3. Hysteroscopic chorionic villus sampling. Chorionic villus sampling was performed with a ureteral catheter under direct hysteroscopic control and ultrasound guidance in eighteen pregnant women at from seven to fourteen gestational weeks. In fifteen cases, the samplings were performed satisfactory. 4. Removal of a lost IUD. Three cases of lost IUD underwent hysteroscopic removal without difficulty. Our results have proved that this scope is a very useful tool for intrauterine operations.
Prenatal diagnoses were performed on six selected pairs of parents known to be carriers of Hb mutations by testing transcervical cells (TCCs) retrieved, prior to chorionic villus sampling (CVS), by aspiration of the cervical mucus from the pregnant mothers at 10-12 weeks of gestation. A concordance between the results of testing chorionic villus cells and isolated clumps of trophoblastic cellular elements was observed in four of the six cases.
A variety of options for prenatal diagnosis are available to the pregnant woman. Maternal serum analyte analysis, performed between 15 and 20 weeks' gestation, provides a screening test for fetal neural tube defects and aneuploidy in low-risk pregnancies. Fetal ultrasound examination is of benefit in high-risk pregnancies. The necessity of prenatal screening in the low-risk patient with an established date of last menstrual period is more controversial. Ultrasound examination can establish gestational age, assess fetal number and position, determine placental location and amniotic fluid volume, and rule out major structural anomalies. Invasive fetal testing, including amniocentesis and chorionic villus sampling, should be offered to women who are 35 years of age or older or who have had abnormal results on noninvasive prenatal screening and in cases in which the parents are carriers of genetic conditions that are amenable to prenatal diagnosis.
Experimental materno-embryonic transfusions with serum that is immunologically active against blood group antigens cause congenital malformations in the rat embryo. In view of the possible increased incidence of vascular disruptive syndromes after chorionic villus sampling (CVS), we investigated the occurrence of materno-fetal transfusions (MFTs) in this procedure. In 18 pregnant women experiencing two needle introductions at CVS, we looked immunohistochemically at the presence of haemoglobin A1-containing maternal erythrocytes in the fetal circulation of the separately collected first and second chorionic villus samples. In 4 of 18 patients (22 per cent), a significant increase of maternal cells was observed in the second sample compared with the first sample, indicating the occurrence of MFT by CVS. On the rare occasion of maternal immunization against fetal antigens, a CVS-associated MFT might provoke immunological damage to the fetus.
Women with single, viable pregnancies at 10 + 5 to 13 + 6 weeks, gestation who requested fetal karyotyping for maternal age, parental anxiety, or a previous history of chromosomal aberration were offered participation in this study. With a transabdominal ultrasound-guided technique, early amniocentesis (EA) was performed on 147 women and chorionic villus sampling (CVS) on 174. Spontaneous fetal loss occurred in 6.8 per cent in the EA group and 1.7 per cent in the CVS group. This difference was significant with a confidence interval (CI) of 0.6-9.6 per cent. There was also a significant difference in the need for repeat testing between the groups. In the EA group a repeat test was required in 19.0 per cent due to culture and sample failures, while 5.2 per cent of the women in the CVS group needed repeat testing because of ambiguous results. This prospective study comparing EA and CVS shows that the risk of fetal loss is higher and repeat testing is needed more after EA.
True chromosomal mosaicism of double trisomy (48,XX, +7, +20) was detected in amniotic fluid cell cultures at 16 and 20 weeks of gestation. No aneuploid cells were found in chorionic villus samples (CVS) by semidirect preparation and long-term culture. High-level ultrasound did not indicate any structural abnormality of the fetus. At 38 weeks of gestation, a phenotypically normal girl was born. She is now 22 months old and normally developed. At birth, various samples were investigated by routine cytogenetic methods or by fluorescence in situ hybridization with the probe p7t1 (umbilical cord blood, placental tissue, umbilical cord fibroblasts, urine sediment) and no abnormal cells could be detected in any of those tissues.
Smith-Lemli-Opitz (RSH) syndrome (SLOS, OMIM 270400) is a relatively common, autosomal recessive disorder of cholesterol biosynthesis with a broad spectrum of phenotypic abnormalities caused by mutations of the 7-dehydrocholesterol reductase gene (DHCR7) on chromosome 11. Prenatal diagnosis can be established by detection of elevated 7-dehydrocholesterol or of SLOS-causing mutations in the DHCR7 gene. We report here our experience with molecular prenatal diagnosis of SLOS. Mutation analysis of the DHCR7 gene was performed in chorionic villus samples of 13 pregnancies of couples with a family history of SLOS and known SLOS genotypes. This approach is accurate and reliable. If facilities for biochemical analysis are not available, or in cases with ambiguous biochemical patterns, molecular prenatal diagnosis is an attractive, alternative option.
Cystic kidneys or renal cystic disease is a morphologic description for an etiological heterogeneous group of disorders ranging from solitary cysts to several forms of multicystic and polycystic kidneys. The combination of the examination of the kidneys and liver, clinical data, family history and the presence of associated anomalies is mandatory to obtain a final diagnosis. The use of prenatal ultrasound to monitor pregnancies at risk for autosomal recessive polycystic kidney disease (ARPKD) is limited because a recurrence can be diagnosed early in pregnancy but may not be excluded. For pregnancies at risk for autosomal dominant polycystic kidney disease (ADPKD), a reliable prenatal diagnosis can only be provided by DNA studies after chorionic villus sampling. Cystic kidneys may present as part of different syndromes. An overview is given of the complex differential diagnosis. Dysplastic (multicystic) kidneys often occur unilaterally. In contrast with polycystic kidneys, diseased liver changes are not present in cystic dysplasia and prenatal ultrasound diagnosis is usually possible.
Prenatal sonographic diagnoses of two cases of severe limb defects after first-trimester chorionic villus sampling (CVS) are presented. Pathological examination after elective termination correlated well with the prenatal sonographic findings. Although the relationship between CVS and limb defects remains controversial, careful ultrasound examination for possible limb defects in cases receiving CVS is recommended.
A late complication of CVS by forceps biopsy is reported. It is the immediate formation of a retroplacental hematoma on the location of the sampling which is revealed by a bleeding across the cervix. During all the pregnancy retroplacental hematoma and bleeding will persist until the delivery by cesarean section at 31 weeks of amenorrhea. Such a late complication has not been reported in the literature.
Invasive prenatal diagnostic techniques such as fetal skin sampling, fetal liver biopsy, and fetal muscle biopsy are now reserved for the diagnosis of congenital disorders not amenable to diagnosis using amniocentesis or CVS. In the next few years, many of these conditions will become detectable by DNA analysis, and the need for these procedures will decline even further.
A discrepancy is reported between the karyotypes of chorionic cells (direct method):46,XX and of cultured amniotic fluid cells: 47,XX, + 18 in a pregnancy of 30 weeks. A stillborn girl, with external signs of trisomy 18 syndrome, was subsequently shown to have a mosaic pattern in both the lymphocytes and the placenta.
Preliminary clinical experience with early amniocentesis is reported. Fifty-two amniocenteses were performed before the end of the 14th week following the last menstrual period. Cytogenetic and biochemical analyses (AFP, AChE) were performed. Increasing experience with amniotic fluid samples containing small-cell populations and the use of combined culture media improved the poor initial results to a 100% level, thus enabling the use of this technique for diagnostic purposes. The sampling technique and the post-procedural evolution of twelve amniocenteses in pregnant women, whose pregnancy is to be continued, are presented. The possibility of performing amniocentesis in early pregnancy is discussed with reference to anatomical aspects (amniotic and chorionic cavity).