Abnormal Fetal Karyotype Research Articles

Elevated day 3 serum follicle stimulating hormone and/or estradiol may predict fetal aneuploidy

Objective: To determine whether baseline serum FSH and/or E 2 concentrations can predict the risk for fetal chromosomal abnormalities. Design: Case control study. Setting: Reproductive technology program at a university hospital. Patient(s): Patients who underwent dilation and curettage (D + C), and whose products of conception were karyotyped. Intervention(s): Patients underwent natural conception or controlled ovarian hyperstimulation followed by intrauterine insemination, in vitro fertilization and embryo transfer, gamete intrafallopian transfer, or zygote intrafallopian transfer. Main Outcome Measure(s): Baseline serum FSH and E 2 concentrations and fetal karyotype. Result(s): Genetic evaluation of 78 D + C specimens revealed 34 normal and 44 abnormal fetal karyotypes. A significantly greater proportion of women with abnormal fetal karyotype had elevated baseline serum FSH (≥15 mIU/mL [RIA] or 10 mIU/mL [Immulite]) and/or E 2 (≥50 pg/mL [Immulite]) compared with women of normal fetal karyotype. Among karyotypically abnormal abortuses, autosomal trisomy was the most common abnormality noted (79.5%), followed by mosaicism (6.8%), triploidy (6.8%), monosomy XO (4.5%), and balanced translocation (2.3%). Conclusion(s): Baseline serum FSH and/or E 2 concentrations may be valuable as predictors of fetal aneuploidy.

Prevalence and significance of isolated fetal choroid plexus cysts detected in early pregnancy by transvaginal sonography in women of advanced maternal age

This study examines the prevalence of isolated fetal choroid plexus cysts (CPCs) detected in early pregnancy by transvaginal sonography in an increased genetic risk population and their association with abnormal fetal karyotype. A prospective study was performed on 1692 pregnant women (>37 years) who underwent transvaginal scan at 11-16 weeks' gestation before genetic amniocentesis. The prevalence of isolated CPCs in our population was 1.48 per cent. An abnormal fetal karyotype was found in one case (4 per cent). It was concluded that if fetal CPCs are apparently isolated, genetic amniocentesis is not mandatory and additional risk factors such as advanced maternal age should be the main indication for fetal karyotyping.

Isolated Mild Fetal Pyelectasis Detected by Transvaginal Sonography in Advanced Maternal Age

In Brief Objective To evaluate the importance and evolution of isolated, mild fetal pyelectasis, detected in early pregnancy by high-resolution transvaginal sonography, and to determine its association with abnormal fetal karyotypes. Methods Transvaginal scan at 11–16 weeks' gestation and transabdominal ultrasound examinations at the time of amniocentesis (16–18 weeks) were performed in 1093 pregnant women undergoing genetic amniocentesis because of advanced maternal age. In 795 cases, transabdominal scans were repeated at 22–24 weeks. Women were excluded if they had a spontaneous abortion, chose to terminate their pregnancy, or declined amniocentesis. Each patient was screened for fetal pyelectasis, defined as an increase in anteroposterior renal pelvic diameter, using cutoff values related to various stages of pregnancy. Results Isolated fetal pyelectasis was detected at the first ultrasound examination in 56 women (5.1%) in early pregnancy, in 32 (2.9%) at the time of amniocentesis, and in 23 (2.9%) at 22–24 weeks' gestation. Two fetuses with diagnoses of mild pyelectasis at the first transvaginal ultrasound demonstrated abnormal karyotypes at amniocentesis. In one case, the pyelectasis disappeared at 22–24 weeks' gestation. Conclusion This retrospective study shows that pyelectasis is more frequently detectable by high-resolution transvaginal sonography in the first half of pregnancy than in the second half. When detected in early pregnancy, the finding is frequently transient and not associated with an increased risk of abnormal fetal karyotypes. Mild fetal pyelectasis detected in early pregnancy by transvaginal sonography can be transient and does not indicate abnormal fetal karyotype.

Isolated mild fetal pyelectasis detected by transvaginal sonography in advanced maternal age

Objective: To evaluate the importance and evolution of isolated, mild fetal pyelectasis, detected in early pregnancy by high-resolution transvaginal sonography, and to determine its association with abnormal fetal karyotypes. Methods: Transvaginal scan at 11–16 weeks’ gestation and transabdominal ultrasound examinations at the time of amniocentesis (16–18 weeks) were performed in 1093 pregnant women undergoing genetic amniocentesis because of advanced maternal age. In 795 cases, transabdominal scans were repeated at 22–24 weeks. Women were excluded if they had a spontaneous abortion, chose to terminate their pregnancy, or declined amniocentesis. Each patient was screened for fetal pyelectasis, defined as an increase in anteroposterior renal pelvic diameter, using cutoff values related to various stages of pregnancy. Results: Isolated fetal pyelectasis was detected at the first ultrasound examination in 56 women (5.1%) in early pregnancy, in 32 (2.9%) at the time of amniocentesis, and in 23 (2.9%) at 22–24 weeks’ gestation. Two fetuses with diagnoses of mild pyelectasis at the first transvaginal ultrasound demonstrated abnormal karyotypes at amniocentesis. In one case, the pyelectasis disappeared at 22–24 weeks’ gestation. Conclusion: This retrospective study shows that pyelectasis is more frequently detectable by high-resolution transvaginal sonography in the first half of pregnancy than in the second half. When detected in early pregnancy, the finding is frequently transient and not associated with an increased risk of abnormal fetal karyotypes.

Discrepancies in cytogenetic findings in chorionic villi.

We present a database and a review of published literature on discrepancies in chorionic villus (CV) diagnostic findings. The review includes 457 cases of discrepancies between CV findings (direct, culture, or both) and the fetus. One hundred and one cases reported normal by CV direct harvest included 30 with abnormal or mosaic abnormal fetal karyotype (30% false negatives). The corresponding number of false negatives for CV culture was only 4 cases out of 133 (3%). Assuming no bias in reporting cases based on site of discrepancy (assumption may not hold), these data imply that the probability of false-negative findings is 10-fold higher by CV direct method compared to CV culture method. We also reviewed recent studies reporting on large series of CV diagnosis. This review revealed that the reported overall frequencies of discrepancies as a percentage of abnormal and mosaic abnormal CV results ranged from 11 to 63% (a mean of 37%). These data, together with recent reports of survival of embryos with reported abnormal karyotypes because of confined placental mosaicism (CPM), raise several questions pertaining to the predictive value of CV sampling and the origin of the discrepancies in the fetal-placental unit. Caution is recommended in counseling patients undergoing CV sampling to provide appropriate follow-up studies in cases of possible discrepancies.

Effect of first-trimester nuchal translucency on second-trimester maternal serum biochemical screening for Down's syndrome.

We evaluated the effectiveness of 10-14 week nuchal translucency measurement in routine ultrasound screening for Down's syndrome, and its effect on the sensitivity of subsequent maternal serum biochemistry. This was an observational study, in which all women attending for antenatal care at a district general hospital were routinely offered a first-trimester nuchal translucency scan and second-trimester quadruple maternal serum biochemistry as screening tests for Down's syndrome. The main outcome measures were abnormal fetal karyotype and the performance of screening tests. A total of 3604 women were scanned in the first trimester of pregnancy. Excluding the cases that did not fit the entry criteria (n = 344, 9.6%) and in which nuchal translucency measurements were not possible (n = 340, 9.4%), a total of 2920 women were screened. A nuchal translucency-derived risk of 1:200 for an aneuploid pregnancy resulted in a 5% (n = 147) screen-positive rate. Screening using this risk enabled the first-trimester detection of five of seven (71%) fetuses with trisomy 21 and 14 of 18 (78%) aneuploid fetuses. Second-trimester maternal serum biochemistry testing was performed in 1904 of the women who had nuchal translucency screening, with a screen-positive rate of 7.5% (n = 143). Only one extra case of Down's syndrome would have been detected by maternal serum biochemistry testing if nuchal translucency screening had been implemented at a risk level of 1:300. This study demonstrates that first-trimester nuchal translucency measurement is effective in routine screening for fetal chromosomal abnormality. Furthermore, the implementation of a nuchal translucency screening program will significantly reduce the positive predictive value of second-trimester maternal serum biochemistry testing.

Pregnancy outcomes following false-positive multiple marker screening tests.

Pregnancy outcomes in women with a false-positive midtrimester multiple marker screening test (MMST) were reviewed. A genetic database was used to identify all women > or = age 30 who had a MMST at 15-20 weeks of gestation, a targeted ultrasound, and amniocentesis, and complete pregnancy outcome data. All patients with an abnormal fetal ultrasound (US) or karyotype were excluded. The incidence of adverse outcomes (defined as fetal death, preterm delivery, or a birth weight less than the 10th percentile for gestational age), in those women with a positive MMST (risk of Down's syndrome > or = 1:190) was compared to the incidence of adverse outcomes in control women with negative MMST. Chi-square analysis and Fisher's exact tests were used for comparisons as appropriate. Complete data was available from 1135 women. Seventy-seven percent were over age 35. Two hundred and forty-six women (22%) had a positive multiple marker test. No significant differences in outcomes were discovered after comparisons to controls: fetal death 1 of 246 (0.4%) versus 12 of 889 (1.3%), p = 0.32; preterm delivery 32 of 246 (13.0%) versus 147 of 889 (16.5%), p = 0.17; birth weight less than the 10th percentile, 9 of 246 (3.7%) versus 30 of 889 (3.4%), p = 0.83. Our data suggest that women > or = age 30 with a false-positive MMST and a normal midtrimester obstetrical sonogram are not at an increased risk for adverse pregnancy outcomes in later gestation.

Development of the fetal tongue between 14 and 26 weeks of gestation: in utero ultrasonographic measurements

Our objective was to establish nomograms for fetal tongue measurements from 14 weeks until mid-gestation by using transvaginal and transabdominal high-resolution ultrasound techniques. A prospective, cross-sectional study was performed on 120 normal singleton pregnancies between 14 and 26 weeks of gestation. Tongue circumference was measured by transvaginal ultrasonography between 14 and 17 weeks, and by abdominal ultrasound between 18 and 26 weeks of gestation. Fetal tongue circumference, as a function of gestational age, was expressed by the regression equation: tongue circumference (mm) = -23.9 + 3.75 x gestational age (weeks). The correlation, r2 = 0.95, was found to be highly statistically significant (p < 0.0001). The normal mean of tongue circumference per week and the 95% prediction limits were defined. During the study period we evaluated two cases with tongue circumference outside these 95% confidence limits: one had microglossia, the other macroglossia, and both were found to be associated with abnormal fetal karyotype. The presented normative data may be helpful in the prenatal diagnosis of suspected congenital syndromes that include, among their manifestations, tongue growth disturbances.

Discrepancies in Cytogenetic Findings in Chorionic Villi

We present a database and a review of published literature on discrepancies in chorionic villus (CV) diagnostic findings. The review includes 457 cases of discrepancies between CV findings (direct, culture, or both) and the fetus. One hundred and one cases reported normal by CV direct harvest included 30 with abnormal or mosaic abnormal fetal karyotype (30% false negatives). The corresponding number of false negatives for CV culture was only 4 cases out of 133 (3%). Assuming no bias in reporting cases based on site of discrepancy (assumption may not hold), these data imply that the probability of false-negative findings is 10-fold higher by CV direct method compared to CV culture method. We also reviewed recent studies reporting on large series of CV diagnosis. This review revealed that the reported overall frequencies of discrepancies as a percentage of abnormal and mosaic abnormal CV results ranged from 11 to 63% (a mean of 37%). These data, together with recent reports of survival of embryos with reported abnormal karyotypes because of confined placental mosaicism (CPM), raise several questions pertaining to the predictive value of CV sampling and the origin of the discrepancies in the fetal-placental unit. Caution is recommended in counseling patients undergoing CV sampling to provide appropriate follow-up studies in cases of possible discrepancies.

A report on 158 cases of transcervical chorionic villus sampling.

Between 1989 and 1994 first trimester transcervical chorionic villus sampling was offered to 158 patients after proper counselling. The gestational age range was 9-12 weeks. The most important indication was advanced maternal age (75.4%). Adequate sampling after two, and a maximum of three attempts, was achieved in 98% and 99.3% of patients respectively. After the first year of the study karyotyping using the direct method alone was successful in 96% of cases. The success of karyotyping cultures was 98%. Excluding one false positive result the rate of fetal karyotypic abnormalities was 4.8%. 5 spontaneous abortions occurred (3.2%), all in patients of advanced maternal age. Moderate or severe vaginal bleeding occurred in 6.7% of the patients. There was no case of chorioamnionitis.

First-trimester chromosome diagnosis by lavage of the uterine cavity.

Fetal karyotyping of trophoblast cells obtained by lavage of the uterine cavity was evaluated on 86 first-trimester irrigation fluid samples. Villus fragments were observed in 72 fluid samples indicating an 83.7 per cent sampling success rate. The amount of villi in these samples ranged from 1 to 32 mg. In most cases, villus fragments showed degeneration of the external syncytiotrophoblast layer and absence of blood vessels. In the first phase of this study (15 samples), a high degree of maternal cell contamination was observed after long-term cultures. In the following phase (71 samples), this obstacle was overcome by the application of a semi-direct method. Chromosome preparations were set up after 24 h incubation of villus fragments and QFQ-banded metaphase spreads were scored for chromosome number and sex. Sixty samples showed the presence of villus fragments and the fetal karyotype was established in 40. Male and female chromosome complements were observed in 16 and 24 cases, respectively. In four cases, an abnormal fetal karyotype was diagnosed. These included trisomy of chromosomes 13, 15, and 16, and one mosaic with trisomy 12. Our results indicate that first-trimester fetal karyotyping might be feasible by a semi-direct method using chorionic villus fragments obtained at intrauterine lavage.

PATHOLOGICAL SIGNIFICANCE OF FIRST-TRIMESTER FETAL NUCHAL OEDEMA

The pathological mechanism that causes the transient phenomenon sonographically defined as "nuchal translucency' is still poorly understood. Seven pregnancies in which the fetuses clearly presented this ultrasonic sign at 10-14 weeks' gestation were terminated because of an abnormal fetal karyotype. The pathological specimens, compared by morphometric analysis with normal fetuses of the same gestational age, showed oedema and dilatation of lymphatic capillary vessels. No particular relationship was found with any structural abnormality. We speculate that nuchal oedema is a transient non-specific phenomenon which is probably related to an early disarrangement of lymphatic connections.

Isolated fetal choroid plexus cysts and karyotype analysis: is it necessary?

The purpose of this study was to evaluate the risk of fetal aneuploidy in the presence of isolated choroid plexus cysts and to evaluate the results obtained from our institution and those reported previously in the English literature. All patients with fetal choroid plexus cysts on prenatal ultrasonography were offered genetic counseling and amniocentesis for fetal karyotyping. Seven of 274 fetuses, 2.6% (95% confidence interval = 1.0 to 5.2%), with isolated choroid plexus cysts were aneuploid. Literature analysis located 23 other reports of 1537 fetuses with isolated choroid plexus cysts; 26 were karyotypically abnormal, 1.7% (95% confidence interval = 1.0 to 2.4%). When evaluating only those patients whose indication for amniocentesis was choroid plexus cysts (i.e., eliminating those patients with advanced maternal age or abnormal serum screening) the risk of having a fetus with trisomy 18 changed little, 1.9% (95% confidence interval = 0.4 to 5.5%). Our data, combined with those of the literature, suggest that the risk of finding an abnormal fetal karyotype in the presence of isolated choroid plexus cysts is at least 1% and may be as high as 2.4%. On the basis of these results, genetic counseling and prenatal diagnosis should be offered to these patients.

Transvaginal sonographic measurement of cisterna magna in fetuses with abnormal karyotype.

The fetal cisterna magna was measured by transvaginal sonography in early pregnancy in 525 pregnant women at increased genetic risk in order to test whether the measurements thus obtained afforded a sonographic marker for abnormal fetal karyotype. The measurements of the cisterna magna increased as pregnancy progressed and showed a good linear correlation with gestational age (r = 0.616; p < 0.001). Chromosome abnormalities were found in 23 fetuses. In all these cases, the cisterna magna measurements were normal, and no differences were observed between fetuses with normal and abnormal karyotype in the different periods tested. While transvaginal sonographic measurement of the cisterna magna is easy to perform in early pregnancy, it is a poor screening test for the detection of abnormal fetal karyotypes.

Studies on the cytogenetic and endocrinologic background of spontaneous abortion

To determine whether chronic menstrual irregularity with elevated LH levels has a role in spontaneous abortion. In 41 consecutively examined women with spontaneous abortions occurring within 11 complete gestational weeks, fetal chromosomal analyses were performed. The differences of endocrinologic background in relation to the result of fetal chromosomal analyses were investigated. Endocrinologic profiles, including menstrual history, basal hormone levels (LH, FSH, and PRL), ovarian morphology on ultrasound, and fetal chromosomal karyotypes. The women with normal fetal karyotypes compared with those with abnormal fetal karyotypes showed higher frequency of menstrual irregularity (47.1% versus 8.3%), elevated basal LH levels (7.42 +/- 5.12 versus 4.41 +/- 1.39 mIU/mL; conversion factor to SI unit, 1.00), and higher frequency of polycystic ovary (41.2% versus 8.3%). Elevated LH-polycystic ovary may be involved in the genesis of spontaneous abortions that are not explainable by fetal chromosomal abnormality.

Prenatal cytogenetic abnormalities: Correlations of structural rearrangements and ultrasonographically detected fetal anomalies

OBJECTIVE: Our purpose was to determine the distribution of karyotypic abnormalities detected at prenatal diagnosis, fetal anomalies, and ability for fluorescent in situ hybridization detection. STUDY DESIGN: Our cytogenetic database from January 1988 to April 1994 was categorized according to type and potential detection by current standard fluorescent in situ hybridization probes. Fetal anomalies and cytogenetic aberrations were compared. RESULTS: A total of 664 cases of abnormal fetal karyotypes were identified from 12,454 prenatal cytogenetic cases (7529 amniocenteses and 4925 chorionic villus sampling) and were classified as autosomal aneuploidy (331), sex aneuploidy (103), polyploidy (38), marker aneuploidy (19) and structural rearrangements (173). Standard fluorescent in situ hybridization probes would have missed 31% of the abnormal cases: 90 aneuploidy, 14 de novo marker aneuploidy, and 65 de novo structural aberrant cases. The 134 cases of structural chromosomal rearrangements with complete ultrasonographic records were further classified as polymorphism (42), familial (43), or de novo (49). Frequency of fetal anomaly detection by ultrasonography in de novo cases ( 22 49 ) was higher than other rearrangements (χ 2 7.4, p = 0.006). CONCLUSION: The contribution of unusual aneuploides (16%) and structural chromosomal rearrangements (26%) in prenatal diagnostic practice is significant. Fetal anomalies were detected by ultrasonography in 45% of the de novo rearrangement cases. Fluorescent in situ hybridization would miss 31% of the abnormal cases.

Perinatal outcome after in vitro fertilisation

A prospective series of 90 consecutive pregnancies (70 singleton, 16 twin and 4 triplet pregnancies) resulting in births of 114 infants after in vitro fertilisation (IVF) at Rigshospitalet were compared to a control group of pregnancies and deliveries in 70 non-IVF infertility patients with singleton pregnancies and 20 women with normal fertility with twin (n = 16) or triplet (n = 4) pregnancies. No differences in the incidence of third trimester pregnancy complications, abnormal fetal karyotypes or malformations were found. The number of women with spontaneous onset of labor and the gestational age at delivery were similar in the IVF and control groups. In singleton deliveries, the birth weight was lower (p < 0.025) in the IVF group (median 3145 g, range 890-4300 g) than in the control group (3399 g, 2592-4850 g), whereas in multiple gestation similar birth weights were found in the IVF and control groups. We conclude that the birth weight in singleton deliveries after IVF is lower than the birth weight in infertility patients treated differently. The cause of this difference remains obscure.

Japanese maternal serum levels of Pregnancy Associated Plasma Protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype

Japanese maternal serum levels of Pregnancy Associated Plasma Protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype

Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype.

To assess the relation between maternal serum pregnancy associated plasma protein A (PAPP-A) in the first trimester and the outcome of pregnancy by karyotype. A retrospective study of PAPP-A levels in blood samples collected prior to chorionic villus sampling. Milan, Italy. Five hundred twenty-two women aged 20 to 47, at 7 to 11 weeks gestation, prior to undergoing chorionic villus sampling. Four hundred forty-five women had a pregnancy with a normal karyotype; in 30 pregnancies the karyotype was abnormal (including 14 cases of Down's syndrome and 7 of trisomy 18). Normal or abnormal fetal karyotype. Serum PAPP-A at 6 to 11 weeks gestation measured by radioimmunoassay. The median value of PAPP-A in the abnormal group was 0.27 multiples of the normal median (MoM). This is significantly lower than the median value in the normal group (1.01 MoM) (95% CI for the difference 0.46-0.84 MoM; P < 0.00001 Mann-Whitney test). There is an association between low levels of PAPP-A in the first trimester with chromosome anomalies. Screening by measurement of PAPP-A might detect 60% of cases of Down's syndrome in the first trimester with a false positive rate of 5%.

Fetal mild idiopathic lateral ventriculomegaly: is there a correlation with fetal trisomy?

Mild idiopathic lateral ventriculomegaly in the mid-trimester fetus can be accurately detected using modern prenatal ultrasonography. Since an abnormal karyotype has been reported in some of these cases, the present prospective study was designed to evaluate, first, the prevalence of mild idiopathic lateral ventriculomegaly in the general obstetric population and, second, to determine the incidence of abnormal fetal karyotype associated with mild idiopathic lateral ventriculomegaly. Eight cases of mild idiopathic lateral ventriculomegaly (0.15%) were detected among 5400 routine prenatal sonographic examinations, between 16 and 22 weeks' gestation. Three newborn infants were found to be normal; in one baby, spontaneous resolution of the lesion occurred in utero, and, among the other five cases, two had an abnormal karyotype: one had Down's syndrome, and one trisomy 18. A review of the English literature revealed that 12% of fetuses with mild idiopathic lateral ventriculomegaly have an abnormal karyotype. Since 3% of the fetuses with Down's syndrome can be visualized in utero with mild idiopathic lateral ventriculomegaly, the calculated risk for Down's syndrome when such lesions appear is about 3%. We, therefore, conclude that karyotypic study is warranted in the mid-trimester fetus with incidental findings of mild idiopathic lateral ventriculomegaly.