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Background: Serum human chorionic gonadotropin (hCG) and hCG free beta-subunit tests are used in combination with unconjugated estriol and alpha-fetoprotein in the triple screen test, and with the addition of inhibin-A in the quadruple marker test for detecting Down syndrome in the second trimester of pregnancy. These tests have a limited detection rate for Down syndrome: approximately 40% for hCG or free beta-subunit alone, approximately 60% for the triple screen test, and approximately 70% for the quadruple marker test, all at 5%, or a relatively high, false-positive rate. New tests are needed with higher detection and lower false rates. Hyperglycosylated hCG (also known as invasive trophoblast antigen or ITA) is a new test. It specifically detects a unique oligosaccharide variant of hCG associated with Down syndrome pregnancies. We evaluated this new Down syndrome-directed test in prenatal diagnosis., Methods: Hyperglycosylated hCG was measured in urine samples from women undergoing amniocentesis for advanced maternal age concerns at 14-22 weeks of gestation, 1448 with normal karyotype and 39 with Down syndrome fetuses., Results: The median hyperglycosylated hCG value was 9.5-fold higher in Down syndrome cases (9.5 multiples of the normal karyotype median). The single test detected 80% of Down syndrome cases at a 5% false-positive rate. Urine hyperglycosylated hCG was combined with urine beta-core fragment (urine breakdown product of serum hCG free beta-subunit), serum alpha-fetoprotein, and maternal age-related risk. This urine-serum combination detected 96% of Down syndrome cases at a 5% false-positive rate, 94% of cases at a 3% false-positive rate, and 71% of cases at a 1% false-positive rate. These detection rates exceed those of any previously reported combination of biochemical markers., Conclusions: Hyperglycosylated hCG is a new base marker for Down syndrome screening in the second trimester of pregnancy. The measurement of hyperglycosylated hCG can fundamentally improve the performance of Down syndrome screening protocols.

Cystic hygromas are developmental abnormalities of the lymphoid system that occur at sites of lymphatic-venous connection, most commonly in the posterior neck. They are frequently associated with karyotypic abnormalities, various malformation syndromes, and several teratogenic agents. The disease course of an infant with cystic hygroma is unpredictable. When diagnosed prenatally, the overall prognosis is poor. Cystic hygroma diagnosed after birth is usually associated with a good prognosis. This article reviews the embryologic, genetic, and pathologic correlates of these lymphatic system abnormalities, as well as the clinical course and outcome of the fetus and newborn with a cystic hygroma. Management strategies are reviewed, including newer nonsurgical therapies for the neonate with a cystic hygroma.

Recent articles by Cuckle et al., Canick et al., and Isozaki et al. have evaluated urine beta-core fragment as a screening test for Down syndrome in second-trimester pregnancies. They found over four-fold elevation of beta-core fragment levels in Down syndrome pregnancies, and between 62 and 88 per cent detection of this trisomy at a 5 per cent false-positive rate. Urine beta-core fragment may be a superior screening test for Down syndrome pregnancies. In the present study, urinary total oestriol has been evaluated as a marker to use in combination with beta-core fragment in screening for Down syndrome pregnancies. The two markers were evaluated separately in relation to the urine creatinine concentration. To amplify screening performance, we evaluated the ratio of beta-core fragment to total oestriol levels (creatinine-independent). beta-core fragment and total oestriol levels were determined (normalized to creatinine, ng/mg creatinine) in urine samples from 480 unaffected and 12 Down syndrome pregnancies, collected consecutively at a single prenatal diagnosis centre. The median beta-core fragment level in Down syndrome cases was 4.5 MOM. Fifty-eight per cent of Down syndrome cases had beta-core fragment levels exceeding the 95th centile of unaffected pregnancies. The median total oestriol level in Down syndrome cases was 0.33 MOM. Forty-two per cent of Down syndrome cases had total oestriol levels exceeding the 95th centile of unaffected pregnancies. We investigated the ratio of the two determinants (beta-core fragment, ng/ml divided by total oestriol, ng/ml) in our sample set. The median beta-core fragment:total oestriol ratio in Down syndrome cases was 13 MOM. Seventy-five per cent of Down syndrome cases had a ratio exceeding the 95th and the 99.5th centile of unaffected pregnancies. Total oestriol complements beta-core fragment in urine screening for Down syndrome pregnancies. A test measuring the ratio of the two urine determinants may be a significant improvement over current serum methods for detecting Down syndrome.

Human chorionic gonadotropin (hCG) free beta-subunit levels were determined in 709 control and 13 Down syndrome urine samples from the second trimester of pregnancy. Results were normalized to urine creatinine concentration and converted to multiples of the unaffected pregnancy medium (MOM). The concentration of free beta-subunit in Down syndrome cases was 3.9 MOM. Seven of 13 Down syndrome pregnancies (54 per cent) had free beta-subunit levels at or above the 95th centile of unaffected pregnancies. Urine free beta-subunit may potentially be useful as a screening test for Down syndrome.

A number of publications have reported an association between the finding of hyperechoic fetal bowel on prenatal sonogram and disorders such as aneuploidy and cystic fibrosis. To define more precisely the significance of this finding, we systematically reviewed the published material on the subject. Based on a total of 357 reported cases, we documented a high prevalence of cystic fibrosis (25.6 per cent) and chromosome abnormality (12.4 per cent) associated with increased bowel echogenicity in the fetus. High rates of intrauterine growth retardation (14.9 per cent), fetal demise (9.0 per cent), and prematurity (15.3 per cent) were also found. The data were obtained from a population at high a priori risk for aneuploidy and included fetuses at 1 in 4 risk for cystic fibrosis reported in two studies. This increased the bias towards an adverse outcome. The rate of complications when a hyperechoic abdomen is noted in a low-risk fetal population has so far not been delineated. Although the high frequency of complications found is of concern and warrants investigation, extrapolation of these risk figures to a fetal population at low a priori risk may not be appropriate.

Objective: Our aim was to develop and evaluate a transabdominal endoscopic technique to visualize the embryo or fetus with thin-gauge needles and submillimetric fiberoptic endoscopes., Methods: Under ultrasonographic guidance, an 18- or 19-gauge thin-wall needle was introduced into the uterus of 28 patients undergoing first-trimester or early second-trimester termination of pregnancy. A 0.7 mm endoscope was threaded through the lumen of the needle after removal of the stylet. Visualization of the embryo-fetus was attempted before 14 weeks' gestation (n = 20). From 16 to 20 weeks (n = 8), the needle and endoscope were directed to the placental insertion of the umbilical cord, and a cordocentesis was performed., Results: Excellent visualization of the surface anatomy of fetuses from 7 to 13 weeks was obtained in 85% of cases (17/20). A diagnosis of Meckel-Gruber syndrome was made at 11 weeks' menstrual age by visualizing postaxial polydactyly and an occipital encephalocele. Endoscopically assisted cordocentesis allowed visualization of the lumen of the umbilical vein and of the blood flow within it., Conclusion: Endoscopic visualization of the embryo or fetus can be performed transabdominally in the first trimester with small-delivered endoscopes. This represents a clear advantage over previous endoscopic approaches to the human pregnancy. Potential applications of this technique include a precise description of fetal anatomy and physiologic features, diagnosis of anomalies, and therapeutic fetal interventions.

Objective: The purpose of this study was to evaluate embryoscopically the effect of placental trauma on the human embryo., Study Design: Patients undergoing elective first-trimester termination of pregnancy underwent transcervical embryoscopy both before and after chorionic villus sampling. If hemorrhagic lesions were not observed on the fetus after chorionic villus sampling, partial placental detachment was performed with a blunt instrument, and the fetus was again observed., Results: Hemorrhagic lesions were observed in 20 of 43 fetuses. In 13 of them, the lesions occurred after placental trauma with the chorionic villus sampling catheter alone (30%), whereas lesions were observed in the remaining seven patients after additional blunt placental disruption. The lesions were located most frequently on the cephalic region, and they grew in size during the observation period. Gestational age or amount of chorionic villus sampling tissue was not different between fetuses with or without lesions., Conclusion: Placental trauma results in embryoscopically demonstrable hemorrhagic lesions on the human embryo. Whereas some of these lesions may be of no consequence, others may lead to permanent changes. If similar lesions occur in deeper tissues, they could cause disruptions in development and conceivably could be related to anomalies reported in infants born to women who have had chorionic villus sampling procedures. Embryoscopy affords the opportunity to study possible mechanisms involved in the occurrence of anomalies.

Many authors have suggested that individuals affected by a terminal 1q deletion display a phenotypically definable and recognizable syndrome. In all of the 27 cases reported to date, the breakpoints were at band q42 or distally to it. To our knowledge, we report the first case of a terminal 1q41 deletion. Diagnosis was made prenatally by amniocentesis, following ultrasonographic diagnosis of omphalocele, cerebral ventriculomegaly, and increased nuchal fold thickness in a 19-week female fetus. Multiple facial and extremity features were consistent with the proposed distal 1q deletion syndrome; omphalocele, however, has not been reported previously. The absence of liver herniation into the omphalocele sac in this case supports the previously reported association of this finding with chromosomal anomalies.

Thirty cases of cervical cystic hygroma were diagnosed in the first trimester of pregnancy. Karyotype analysis was available in 29 (97 per cent). Fifteen (52 per cent) had a chromosomal abnormality. The ultrasound appearance was described as posterior cervical, lateral cervical, or cervical hygroma with hydrops. Of the 14 euploid embryos, six were electively aborted, two are undelivered, and six have been delivered as phenotypically normal infants. In cases in which the chromosomes were normal and the pregnancy continued, all lesions resolved by 18 weeks.

Amniocentesis was performed in 1038 patients with elevated maternal serum alpha-fetoprotein (MSAFP) concentrations. Patients were divided into two groups based upon the amniotic fluid AFP concentration. Group 1 (N = 964) had a normal amniotic fluid AFP concentration and group 2 (N = 74) had elevated amniotic fluid AFP. Fetal chromosomal results were reviewed from the study population, with the finding of eight major fetal chromosomal abnormalities. Of the eight fetal chromosomal abnormalities, five were associated with elevated amniotic fluid AFP and three were associated with normal amniotic fluid AFP. The sensitivity and specificity of elevated amniotic fluid AFP concentrations in screening for a fetal chromosomal abnormality were 62.5 and 93.3%, respectively. In women with elevated MSAFP but normal amniotic fluid AFP concentrations, the probability of a major fetal chromosomal abnormality is extremely small.

Thirty cases of fetal hydrocephalus were diagnosed at the perinatal ultrasound unit of Yale-New Haven Medical Center during a 41 month period. Prenatal ultrasound was found to be highly valuable in the detection of fetal hydrocephalus. However, the antenatal detection of associated anomalies was not as uniformly successful. The importance of a complete sonographic evaluation of intracranial and extracranial anatomy is stressed, as 10 patients with documented hydrocephalus (37%) had associated intracranial anomalies and 17 patients (63%) had associated extracranial anomalies. In this series, isolated hydrocephalus without associated anomalies occurred in only four patients (15%).

Chorionic villus sampling is a method of prenatal diagnosis in the first trimester of pregnancy in which tissue for genetic study is aspirated from the developing placenta by means of a catheter inserted transcervically under the guidance of ultrasonography. In this seven-center study, we compared the safety and efficacy of chorionic villus sampling in 2278 women with those of amniocentesis at 16 weeks' gestation in 671 women. Both groups were made up primarily of well-educated private patients; they were recruited in the first trimester of pregnancy and had viable pregnancies verified by ultrasound examination. Cytogenetic diagnoses resulted from 97.8 percent of the chorionic villus sampling procedures and 99.4 percent of the amniocenteses (P less than 0.05); aneuploidy was found in 1.8 and 1.4 percent, respectively, of the cases in which diagnoses were made. Of the women who underwent chorionic villus sampling, 17 (0.8 percent) subsequently had an amniocentesis because the diagnosis was ambiguous. Two of the diagnoses of aneuploidy (one tetraploidy, one trisomy 22) were later proved to be incorrect. On the basis of pediatric examination of the infants subsequently born to the women in the sample, there were no errors in the determination of sex or the identification of the major trisomies (21, 18, and 13). The rate of combined losses due to spontaneous and missed abortions, termination of abnormal pregnancies, stillbirths, and neonatal deaths was 7.2 percent in the group that underwent chorionic villus sampling and 5.7 percent in the group that had amniocentesis. After adjustment for slight differences in gestational and maternal age, the total loss rate for the women in the chorionic villus sampling group exceeded that for the amniocentesis group by only 0.8 percentage points (80 percent confidence interval, -0.6 to 2.2). The rate of loss of chromosomally normal fetuses after chorionic villus sampling was 10.8 percent among women in whom three or four attempts were made to place the transcervical catheter, as compared with 2.9 percent in those in whom only one attempt was necessary (P less than 0.01). There were no serious maternal infections among the women in this study or among an additional 1990 women who underwent chorionic villus sampling (upper 95 percent confidence limit, 0.08 percent). We conclude that chorionic villus sampling is a safe and effective technique for the early prenatal diagnosis of cytogenetic abnormalities, but that it probably entails a slightly higher risk of procedure failure and of fetal loss than does amniocentesis.

Although the risk of Down's syndrome increases with maternal age, women under 35 bear about 80 percent of the infants born with this condition. We prospectively investigated the utility of measuring maternal serum alpha-fetoprotein during the second trimester in women under 35 in order to identify pregnancies in which the fetus was affected with Down's syndrome. Over a two-year period, 34,354 women in this age group were screened. Amniocentesis was offered when the risk of Down's syndrome, calculated as a function of maternal age and maternal serum alpha-fetoprotein concentration adjusted for maternal weight and race, was 1:270 or higher, the risk for a 35-year-old woman. This threshold was exceeded in 1451 women in whom gestational age was confirmed by ultrasound; 9 women in this group had a fetus with the syndrome. In three women whose fetuses had trisomy 18 and one whose fetus had trisomy 13, the calculated risk of Down's syndrome was 1:270 or higher. Thus, among women in whom the risk exceeded our cutoff point, 1 in 161 were found to have a pregnancy in which the fetus was affected with Down's syndrome; the figure was 1 in 112 for all autosomal trisomies. Eighteen pregnancies involving Down's syndrome, three involving trisomy 18, and two involving trisomy 13 were not associated with a calculated risk above the cutoff point. The available data indicate that in our population, using a cutoff for risk at which 5 percent of women under 35 are offered amniocentesis, we will detect one quarter to one third of pregnancies in which the fetus has Down's syndrome.

Methylmalonic acidemia due to deficient synthesis of 5'-deoxyadenosylcobalamin was discovered in a mid-term fetus by culture of amniotic-fluid cells. Elevated concentrations of methylmalonic acid were also found in amniotic fluid and maternal urine. Treatment during the last nine weeks of gestation with large doses of vitamin B12 given to the mother reversed the increasing maternal excretion of methylmalonic acid, which was 23 mug per milligram of creatinine at 31 weeks' gestation. Just before delivery, the mother was excreting 5 mug, two to three times normal. At birth the methylmalonic acid content of the baby's urine (67 mug per milligram of creatinine) and serum (2.0 mug per milliliter) was only moderately elevated, and serum vitamin B12 concentration was very high. Acid levels rose in serum and urine in response to oral protein loading, but subsided after vitamin B12 administration. The infant is developing normally on a restricted protein diet alone at present. Prenatal therapy of methylmalonic acidemia is possible with large amount of vitamin B12 administered to the mother.

The frequency of chromosomal abnormalities in infants with congenital heart disease has been estimated from postnatal clinic data to be 5% to 10%. Over an 18-month period we performed fetal echocardiograms on 502 fetuses and found cardiac anomalies in 34. Eleven of these fetuses (32%) had abnormal chromosomes. This marked discrepancy from the data found in the pediatric literature may relate to nonviable fetuses identified in utero, who escape pediatric case identification. We conclude that in cases of fetal heart disease the workup should include either amniocentesis or fetal blood sampling for chromosome analysis. The information can be used for complete parental counseling and for managing delivery and neonatal care.

Placental membrane anatomy was evaluated after delivery in 65 twin pregnancies undergoing genetic amniocentesis with amniotic fluid alpha-fetoprotein and acetylcholinesterase determinations when indicated. Each twin member in the 57 uncomplicated twin pregnancies was found to have an amniotic fluid alpha-fetoprotein concentration similar to that of singleton pregnancies of an equivalent gestational age. Eight twin pregnancies were found to be discordant for fetal anomalies associated with an elevated amniotic fluid alpha-fetoprotein and acetylcholinesterase level. The amniotic fluid alpha-fetoprotein concentration in the unaffected fetus in these eight cases was found to be dependent on placental membrane structure. Of the five discordant twin pregnancies with diamnionic-dichorionic placentas, all unaffected twins demonstrated an amniotic fluid alpha-fetoprotein concentration within the normal range for gestational age with a normal acetylcholinesterase level. In three twin pairs with diamnionic-monochorionic placentas, the unaffected twin member had significantly elevated amniotic fluid alpha-fetoprotein and acetylcholinesterase levels, which suggested diffusion of alpha-fetoprotein and acetylcholinesterase through the amnion-amnion interface.

We describe a potential screening method for the second trimester detection of the fetus with Down syndrome by the use of standard sonographic biometry. Retrospective assessment of the biparietal diameter, femur length, and biparietal diameter/femur length ratio in 55 fetuses with Down syndrome and 544 control fetuses was performed at two medical centers. Adequate numbers of cases and controls were available to permit statistically significant comparisons between the groups at 15 to 23 weeks' gestation. Fetuses with Down syndrome displayed no statistically significant differences in the cephalic index or the biparietal diameter compared with controls at a given gestational age. Significant femur length shortening was observed, but the greatest statistical difference was noted for the biparietal diameter/femur length ratio. This ratio was found to decrease with gestational age in the normal population and was consistently elevated in the Down syndrome population (compared with control) throughout the second trimester. With a cutoff value of 1.5 SD above the normal population mean for the biparietal diameter/femur length ratio, 50% to 70% of fetuses with Down syndrome could be identified in 6% of the total population (p less than 0.0001). This preliminary study suggests that the biparietal diameter/femur length ratio may prove superior to current Down syndrome screening methods and, as a third independent variable, may significantly enhance the sensitivity and specificity of combined maternal age/maternal serum alpha-fetoprotein screening modalities.

During a two-year period, nine cases of cephalocele were evaluated at the authors' perinatal ultrasound unit. There was one false positive and one false negative diagnosis. In five cases, multiple anomalies were present; three as part of the amnion rupture sequence. The obstetric management consisted of elective termination of pregnancy in five cases and cesarean section in four. The value of sonography in the diagnosis of cephalocele and associated syndromes and malformations is discussed. A plan of management and counseling based upon current understanding of prognosis is presented.

Cytogenetic studies on fetal blood cells obtained at 18-25 weeks gestation have provided information for decision making in 25 cases identified as being at high risk of having an abnormal fetus. In particular, in the 21 cases studied to consider the possibility of true mosaicism, confirmation in fetal blood was obtained in three, one of which presented as a pseudomosaic on the original amniotic fluid cell study. Fetal blood was also informative in two cases (one positive and the other negative) in which a diagnosis of the fragile X syndrome was being considered. Furthermore, when high risk pregnancies presented late in gestation (21-24 weeks), these methods allowed for a rapid cytogenetic diagnosis. The procedure has proved useful in most of these cases since the couples involved had indicated that they would probably have terminated the pregnancy without the reassurance of normal fetal lymphocyte studies. Since the technique carries a much higher risk of pregnancy loss than does amniocentesis, its use should only be considered when there are compelling indications.

Fetal ventriculomegaly is an abnormal increase in the size of the lateral cerebral ventricles. Presented here is a case of fetal ventriculomegaly in which there was spontaneous intrauterine improvement in its severity.