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Nonimmune hydrops fetalis (NIHF) has a striking appearance on ultrasonography and is classically defined by the presence of pathologic fluid accumulation in at least two fetal sites, including the ...

Current prenatal screening practices and the complexity of genomic science create a risk that early, noninvasive fetal genetic sequencing will be integrated into care without the robust informed consent processes necessary for respecting women’s autonomy.

Investigations of noninvasive prenatal screening for aneuploidy by analysis of circulating cell-free DNA (cfDNA) have shown high sensitivity and specificity in both high-risk and low-risk cohorts. However, the overall low incidence of aneuploidy limits the positive predictive value of these tests. Currently, the causes of false positive results are poorly understood. We investigated four pregnancies with discordant prenatal test results and found in two cases that maternal duplications on chromosome 18 were the likely cause of the discordant results. Modeling based on population-level copy-number variation supports the possibility that some false positive results of noninvasive prenatal screening may be attributable to large maternal copy-number variants. (Funded by the National Institutes of Health and others.)

Researchers have reported sequencing a fetal genome from cell-free fetal DNA in a pregnant woman's blood, heralding the possibility of performing whole-genome sequencing as early as the first trimester of pregnancy. This innovation raises ethical and policy questions.

Meconium Ileus in a Neonate with Cystic Fibrosis In a newborn infant with a prenatal diagnosis of cystic fibrosis, abdominal distention and emesis developed at 12 hours of age. A radiograph of the abdomen and a water-soluble contrast enema suggested a diagnosis of meconium ileus.

The incidence of familial dysautonomia has decreased precipitously since population screening began in 2001. Dr. Barron Lerner writes that the potential disappearance of new cases of a disease raises profound questions.

Group B streptococcal disease is one of the most common infections in the first week after birth. In 2002, national guidelines recommended universal late antenatal screening of pregnant women for colonization with group B streptococcus to identify candidates for intrapartum chemoprophylaxis.We evaluated the implementation of the guidelines in a multistate, retrospective cohort selected from the Active Bacterial Core surveillance, a 10-state, population-based system that monitors invasive group B streptococcal disease. We abstracted data from the labor and delivery records of a stratified random sample of live births and of all cases in which the newborn had early-onset group B streptococcal disease (i.e., disease in infants7 days of age) in 2003 and 2004. We compared our results with those from a study with a similar design that evaluated screening practices in 1998 and 1999.We abstracted records of 254 births in which the infant had group B streptococcal disease and 7437 births in which the infant did not. The rate of screening for group B streptococcus before delivery increased from 48.1% in 1998-1999 to 85.0% in 2003-2004; the percentage of infants exposed to intrapartum antibiotics increased from 26.8% to 31.7%. Chemoprophylaxis was administered in 87.0% of the women who were positive for group B streptococcus and who delivered at term, but in only 63.4% of women with unknown colonization status who delivered preterm. The overall incidence of early-onset group B streptococcal disease was 0.32 cases per 1000 live births. Preterm infants had a higher incidence of early-onset group B streptococcal disease than did term infants (0.73 vs. 0.26 cases per 1000 live births); however, 74.4% of the cases of group B streptococcal disease (189 of 254) occurred in term infants. Missed screening among mothers who delivered at term accounted for 34 of the 254 cases of group B streptococcal disease (13.4%). A total of 61.4% of the term infants with group B streptococcal disease were born to women who had tested negative for group B streptococcus before delivery.Recommendations for universal screening were rapidly adopted. Improved management of preterm deliveries and improved collection, processing, and reporting of culture results may prevent additional cases of early-onset group B streptococcal disease.

A 37-year-old woman, gravida 1, seeks prenatal care at 8 weeks' gestation. Her family history and medical history are unremarkable. What would you advise regarding her risk of fetal chromosomal abnormalities such as Down's syndrome and her options for prenatal screening and diagnosis?

A 29-year-old woman was transferred to this hospital at 38 weeks 4 days of gestation because of a large cystic structure that had been detected by ultrasonography in the fetal oral cavity and appeared to obstruct the airway. The placenta was anterior, and a uterine fibroid was seen. A management decision was made.

Cell-free fetal DNA testing permits earlier detection of common trisomies and generally provides earlier information about a fetus's sex. But with its clinical utility in the general population uncertain, such testing is drifting into routine practice ahead of the evidence.

In this issue of the Journal, three research teams report on the application of the microarray in prenatal and reproductive genetics.1–3 These reports highlight the power and complexity, and some of the pitfalls, of using new genomic technology in clinical practice. Chromosomal microarrays can detect almost all the chromosomal imbalances detected in conventional cytogenetic analysis in addition to submicroscopic deletions and duplications that are at least 1 kb in size, termed copy-number variants. These variants are typically classified as benign, pathogenic, or of uncertain clinical significance.4 Chromosomal microarrays are recommended as the first-tier diagnostic test for the postnatal evaluation . . .

In 1996 the American College of Obstetricians and Gynecologists, along with the American Academy of Pediatrics and the Centers for Disease Control and Prevention, recommended one of two courses for healthcare providers toidentify women who should receive intrapartum antibiotic prophylaxis to prevent group B streptococcal (GBS) disease in infants aged 1 week or less: screening by culture or assessment of clinical risk factors. These two approaches have now been compared in a retrospective cohort study of approximately 630,000 live births. Study cases were accessed in the years 1998-1999 in eight geographic areas of the United States where active surveillance for GBS infection was under way. A random sample of these areas yielded 5144 births. The 312 cases of early onset GBS disease translated into an overall incidence of 0.5 case per 1000 live births. No clinical risk factors for transmitting GBS disease were identified in 62% of cases. More than half of the women in the overall population (52%) were screened before delivery. On univariate analysis, prenatal culture screening correlated with a lower risk of early onset GBS disease than was the clinical risk-based approach; the relative risk (RR) was 0.48. The most prominent risk factors were a previous infant having GBS disease and intrapartum fever. GBS bacteriuria during pregnancy was not a factor, but more than 80% of all women with bacteriuria received intrapartum antibiotics. Screening continued to be associated with a reduced risk on multivariate analysis (RR, 0.46). Screening protected full-term infants when analyzed separately. Intrapartum antibiotic treatment was 89% effective in preventing early onset GBS disease in culture-positive women. It was estimated that, assuming perfect implementation of either strategy, intrapartum antibiotics would be used in 31% of screened women and 29% of those having risk-based assessment. These findings suggest that it makes sense to further consider a recommendation favoring universal screening to prevent GBS disease in newborn infants.

Standard prenatal screening for trisomy 21 (Down's syndrome) is based on a combination of maternal age, maternal serum biomarkers, and fetal ultrasonographic findings. Such screening can identify 70 to 90% of fetuses with trisomy 21 with a false positive rate of 2 to 5%.1 Screening that is based on analysis of cell-free DNA (cfDNA) in maternal plasma is now available through commercial providers in more than 60 countries around the world.2 However, although the sensitivities and specificities obtained through this approach are high,3 there is still much debate as to how this screening should be offered. Most large studies evaluating . . .

Screening of maternal serum to identify fetuses with Down's syndrome is now routinely offered during the second trimester of pregnancy. Prenatal screening by means of serum assays or ultrasonographic measurements, either alone or in combination, may also be possible in the first trimester.We measured serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin (hCG), the free beta subunit of hCG, and pregnancy-associated protein A in 4412 women (82 percent of whom were 35 years of age or older) who came to 16 prenatal diagnostic centers for chorionic-villus sampling or early amniocentesis at 9 to 15 weeks of gestation. Ultrasound measurements of fetal nuchal translucency were also reported. Fetal chromosomal analysis was performed in all pregnancies. Altogether, there were 61 fetuses with Down's syndrome.A total of 48 pregnancies affected by Down's syndrome and 3169 unaffected pregnancies were identified before 14 weeks of gestation; the rates of detection of Down's syndrome for the five serum markers were as follows: 17 percent for alpha-fetoprotein, 4 percent for unconjugated estriol, 29 percent for hCG, 25 percent for the free beta subunit of hCG, and 42 percent for pregnancy-associated protein A, at false positive rates of 5 percent. The results of the measurements of serum hCG and its free beta subunit were highly correlated. When used in combination with the serum concentration of pregnancy-associated protein A and maternal age, the detection rate was 63 percent for hCG (95 percent confidence interval, 47 to 76 percent) and 60 percent for its free beta subunit (95 percent confidence interval, 45 to 74 percent). Measurements of nuchal translucency varied considerably between centers and could not be reliably incorporated into our calculations.Screening for Down's syndrome in the first trimester is feasible, with use of measurements of pregnancy-associated protein A and either hCG or its free beta subunit in maternal serum.

Background. In screening for Down's syndrome in the second trimester of pregnancy, the concentrations of alpha-fetoprotein, the β subunit of human chorionic gonadotropin, and intact human chorionic gonadotropin in maternal serum are widely used markers. We investigated a new marker, dimeric inhibin A, and compared its predictive value with that of the established markers. Methods. Serum samples were obtained at 7 to 18 weeks of gestation from 58 women whose fetuses were known to be affected by Down's syndrome, 32 whose fetuses were affected by trisomy 18, and 438 whose fetuses were normal, and the samples were analyzed for each marker. Individual serum concentrations of each marker were converted to multiples of the median value at the appropriate length of gestation in the women with normal pregnancies, and rates of detection of Down's syndrome by screening for inhibin A in various combinations with the other markers were estimated by multivariate analysis. Results. In the women with fetuses affected by Down's syndrome, the serum inhibin A concentrations were 2.06 times the median value in the women with normal pregnancies (P

DNA analysis of peripheral-blood leukocytes is routinely used to demonstrate mutations in the dystrophin gene in patients with Duchenne's or Becker's muscular dystrophy. In approximately 35 percent of patients, DNA studies are not informative; in these patients immunochemical analysis of a muscle-biopsy specimen can determine whether dystrophin, the protein product of the gene for Duchenne's dystrophy, is present at reduced levels or absent. DNA analysis can be performed in amniocytes or chorionic-villus cells to identify mutations of the dystrophic gene prenatally, but immunochemical testing for dystrophin cannot be performed because the protein is not expressed in these cells.To circumvent this limitation in prenatal diagnosis, we induced myogenesis in 21 cultures of skin fibroblasts, 49 amniocyte cultures, and 6 chorionic-villus cell cultures by infecting the cells with a retrovirus vector containing MyoD, a gene regulating myogenesis. Transfection of MyoD into cells that do not normally develop into muscle cells results in the production of a protein that switches on myogenesis. We performed immunocytochemical analysis for dystrophin in the MyoD-converted muscle cells.We found that 60 of 61 myotube cultures from subjects with no family history of Duchenne's dystrophy expressed dystrophin. Both myotube cultures from the two patients with Becker's dystrophy also expressed dystrophin, but all cultures from nine patients and two fetuses with Duchenne's dystrophy were dystrophin-deficient.Immunocytochemical analysis of dystrophin in genetically altered non-muscle cells is feasible and may be applicable to the prenatal and postnatal diagnosis of Duchenne's muscular dystrophy when conventional DNA analysis is not informative.

Currently, the most common techniques for prenatal diagnosis are amniocentesis, performed between 14 and 22 weeks' gestation, and chorionic-villus sampling, performed between 14 and 20 weeks' gesta...

Cystic fibrosis is a common, severe autosomal recessive disease caused in a majority of cases by a three-nucleotide deletion (delta F508) in the cystic fibrosis transmembrane regulator gene. Current methods of prenatal diagnosis involve chorionic-villus sampling or amniocentesis. In vitro fertilization and diagnosis during embryonic development before implantation would allow only unaffected embryos to be selected for transfer to the uterus, thereby avoiding the need to terminate a pregnancy.Preimplantation diagnosis of cystic fibrosis was attempted in the cases of three couples, both members of which carried the delta F508 deletion. In vitro fertilization techniques were used to recover oocytes from each woman and fertilize them with her husband's sperm. Three days after insemination, embryos in the cleavage stage underwent biopsy and removal of one or two cells for DNA amplification and analysis.Only two oocytes from one woman were fertilized normally; DNA analysis of one of the embryos failed and cystic fibrosis was diagnosed in the other (i.e., it was homozygous for delta F508), so neither was transferred. The oocytes of each of the other two women produced noncarrier, carrier, and affected embryos. Both couples chose to have one noncarrier embryo and one carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes.Preimplantation diagnosis of the delta F508 deletion causing cystic fibrosis is possible through in vitro fertilization, biopsy of a cleavage-stage embryo, and amplification of DNA from single embryonic cells. This approach should be equally applicable to other single-gene diseases in which the defect has been identified. Analysis of a series of pregnancies, however, will be required to assess the method adequately.

Approximately 35 percent of all cases of Down's syndrome in fetuses can be detected by measuring maternal serum alpha-fetoprotein during the second trimester in the general population of pregnant women. Recent case-control studies indicate that this detection rate could be approximately doubled by measuring serum levels of unconjugated estriol and chorionic gonadotropin, which are abnormally low and abnormally high, respectively, in women carrying fetuses affected by Down's syndrome.We prospectively screened 25,207 women and adolescents in the second trimester of pregnancy and assigned each a risk of fetal Down's syndrome with an algorithm that took into account measurements of all three serum markers in combination with maternal age. On this basis, 1661 subjects (6.6 percent) were initially assigned a second-trimester risk of fetal Down's syndrome of at least 1 in 190, and 962 (3.8 percent) were offered amniocentesis for chromosomal analysis after verification of gestational age. Gestational age was determined on the basis of the first day of the last menstrual period or, when available, by ultrasonography.Among the 760 women and adolescents who chose amniocentesis, 20 cases of fetal Down's syndrome were detected, along with 7 other chromosomal disorders. There was 1 additional case of fetal Down's syndrome among the 202 women who chose not to have amniocentesis. The rate of detection of Down's syndrome was thus 58 percent (21 of 36 expected cases), and the frequency of identifying a fetus with Down's syndrome in women undergoing amniocentesis was 1 per 38 amniocenteses (95 percent confidence interval, 1 in 25 to 1 in 62).Measuring serum alpha-fetoprotein, chorionic gonadotropin, and estriol is more effective in screening for fetal Down's syndrome than measuring maternal serum alpha-fetoprotein alone. Such an expanded protocol can readily be incorporated into existing prenatal screening programs.

Background. Chorionic-villus sampling is done in early pregnancy to obtain fetal cells for the prenatal diagnosis of genetic and chromosomal defects. Transcervical chorionic-villus sampling has been shown to be safe and effective in national trials. Recently, an alternative transabdominal technique has been suggested as potentially easier and safer. Methods. From April 1987 through September 1989, we prospectively compared transcervical and transabdominal chorionic-villus sampling in 3999 women with singleton pregnancies in whom the risk of a genetically abnormal fetus was increased. Women between 7 and 12 weeks of gestation underwent ultrasonographic evaluation of placental and uterine position. Those with active vaginal infections, active bleeding, or cervical polyps were excluded. If the obstetrician thought either sampling procedure was acceptable, the woman was asked to consent to random assignment to one of the two procedures. Both groups were followed to determine the outcome of pregnancy ...