The epidemic of abnormal copy number variant cases missed because of reliance upon noninvasive prenatal screening.

OBJECTIVE: To assess the implications of increasing utilization of noninvasive prenatal screening (NIPS), which may reach 50% with the concomitant decrease in diagnostic procedures (DPs) for its impact on detection of chromosomal abnormalities. METHODS: We studied our program's statistics over 5 years for DPs and utilization of array comparative genomic hybridization (aCGH). We then modeled the implications in our program if DP had not fallen and nationally of a 50% DP and aCGH testing rate using well-vetted expectations for the diagnosis of abnormal copy number variants (CNVs). RESULTS: Our DP fell 40% from 2013-2017. Utilization of aCGH for DP nearly tripled. We detected 28 abnormal CNVs. If DP had not fallen, we likely would have detected 60. With 4 million US births per year, 2 million DPs would detect 30 000 abnormal CNVs and 4000 standard aneuploidies. At a 1/500 complication-pregnancy loss rate, the detection/complication ratio is 8.5/1. CONCLUSIONS: Noninvasive prenatal screening has significantly changed the practice of prenatal screening. However, while increasing the detection of Down syndrome, the concomitant decrease in DP and lack of aCGH results in missing many more abnormalities than the increase in Down syndrome and complications of DP combined. From a public health perspective, such represents a missed opportunity for overall health care delivery.

Screening and Testing in Multiples.

The choice of screening or invasive procedure in twin pregnancies is a personal choice of whether the patient wishes to take a small risk of having a baby with a serious disorder versus a small risk of having a complication because she wishes to avoid that. How to interpret such risks has profound effects on the perceived value of techniques, either leading to a decision to screening or going directly to chorionic villus sampling. There are profound issues surrounding the data and the interpretation of the data. No single short review can exhaustively examine all of the issues.

Integrating Microarrays into Routine Prenatal Diagnosis: Determinants of Decision Making.

OBJECTIVES: The explosion in genetic technologies, including array comparative genomic hybridization (aCGH), has increased the complexity of genetic counseling. We now offer chorionic villus sampling (CVS) and aCGH to all first-trimester patients, as this allows the prenatal diagnosis of an additional 1% of anomalies not otherwise detectable and can detect genetic copy number variants at a much higher resolution than conventional cytogenetics. Here, we explored some of the determinants of how patients are deciding to use or not use this new technology and evaluate risk-benefit analyses for that decision. METHODS: This is a retrospective case-control study of singleton and multiples pregnancies at our center. Those having aCGH testing along with CVS were defined as 'testers' and those who declined aCGH but had the CVS were 'nontesters'. RESULTS: Demographic data of 181 educated women who chose CVS were compared. Among those carrying singletons (n = 144), older women, defined as over 35 years of age (or 'advanced maternal age'; AMA), were more likely to choose the aCGH than younger women. Further, women who had a prior history of genetic testing and who wanted to know the gender of the fetus were more likely to choose the aCGH test. In women carrying multiples (n = 37), AMA ceases to be a predictor of choice. Having had prior genetic counseling remains a strong predictor for choosing aCGH, as does wanting to know the gender of the fetus. Neither prior abortions nor having prior children were significant for women carrying singletons or multiples. CONCLUSION: Offering pregnant couples an individualized choice regarding aCGH seems an appropriate approach. There are discrete patterns associated with the choice of taking the aCGH that varied depending on whether the patient was carrying a singleton or multiples.

Genetics: update on prenatal screening and diagnosis.

There have been tremendous advances in the ability to screen for the "odds" of having a genetic disorder (both mendelian and chromosomal). With microarray analyses on fetal tissue now showing a minimum risk for any pregnancy being at least 1 in 150 and ultimately greater than 1%, it is thought that all patients, regardless of age, should be offered chorionic villus sampling/amniocentesis and microarray analysis. As sequencing techniques replace other laboratory methods, the only question will be whether these tests are performed on villi, amniotic fluid cells, or maternal blood.

Fetal reduction: 25 years' experience.

Fetal reduction (FR) began in the 1980s to salvage the pregnancies of couples needing fertility therapy who were finally successful but with too many fetuses. Since then, it has gone from a rarity performed in only the highest risk situations to an integral fail-safe of infertility practice. Our understanding of the problems of multiple and premature births has increased - even twins carry 4-5 times more risk than singletons. Evaluation of fetuses before FR has permitted more intelligent choices and improved resultant outcomes. We now perform chorionic villus sampling in approximately 85% of cases, obtain fluorescent in situ hybridization (FISH) results overnight, and then perform FR the next day. Decisions about which to reduce prioritize anomalies, but now can include fetal gender in the decision process, as couples are now just as likely to want girls as boys. In Mendelian cases, sophisticated molecular analyses permit diagnoses before FR, and new uses such as paternity analysis can be performed. Ethical arguments have also evolved; as with many technologies in which the start was for only 'life or death cases', FR has also moved into 'quality of life' issues. FR of twins to a singleton now compromise about 30% of our cases.

Paternity balancing.

BACKGROUND: Gestational carriers and egg donors have been used by 'traditional' and now increasingly, gay couples. Three gay male couples, all using egg donors and gestational carriers with semen from both partners, had triplets. All desired reductions to twins for the standard medical indications, but requested, if reasonably possible, to have twins with one fathered by each partner. METHODS: Following our usual clinical protocol, we performed chorionic villus sampling at 12 weeks on all fetuses obtaining FISH and karyotype. For paternity analysis, 14 polymorphic molecular markers on villi were compared to DNA samples from the two men to include or exclude each. RESULTS: Standard assessments were all normal. Paternity testing showed that one partner fathered two of the triplets, and the other one. In all cases, one of the 'twins' was reduced with good clinical outcomes ensuing. CONCLUSIONS: Paternity balancing increases options for satisfying family planning desires of gay male couples. We believe it comparable to gender preferences in reductions, i.e. it can be considered but only completely subservient to any clinical criteria. Paternity balancing raises similar ethical issues as reduction with gender preferences, but may increase patient autonomy and mainstream acceptance of stable, gay families.

Detection of genetic abnormalities by using CVS and FISH prior to fetal reduction in sonographically normal appearing fetuses.

OBJECTIVE: To examine the ability of chorionic villus sampling (CVS) and fluorescence in situ hybridization (FISH) to detect aneuploidy before first trimester fetal reduction (FR) in sonographically normal-appearing fetuses. METHODS: A retrospective review of 470 patients referred to our unit for FR from January 2007-March 2011. Prenatal diagnosis was offered to all. FR was performed after next-day FISH results. Abnormalities were categorized by ultrasound, FISH, and/or karyotype. Sensitivity, specificity, positive predictive value, and negative predictive value of pre-FR FISH were calculated. RESULTS: Four hundred thirty-two of 470 patients seen were first trimester. 24/432 (5.2%) were excluded for abnormal ultrasound findings, including nuchal translucency (NT) > 3.0 mm, and 360 (88.2%) underwent CVS before FR. Ten fetuses were then excluded for euploid sex mosaicism. 10/350 (2.9%) patients with normal ultrasounds had abnormal FISH confirmed by karyotype. 9/350 (2.6%) patients with normal FISH had an abnormal karyotype necessitating follow up amniocentesis in which the clinically relevant discordancy was confirmed in one case (1/350, 0.3%). Pre-FR FISH had a 90% sensitivity, 99.4% specificity, 83.3% positive predictive value, and 99.7% negative predictive value. CONCLUSIONS: 3.1% of patients with normal-appearing fetuses prior to first trimester FR had a fetus with an abnormal karyotype of which FISH detected 90%. CVS with FISH prior to FR adds significant information that can guide reduction decisions.

Evolution of gender options in multiple pregnancy management.

OBJECTIVE: Fetal reduction (FR) in multiples dramatically improves outcomes. We prioritize FR decisions for health and historically declined to factor gender. As male preferences apparently diminished, our bioethicist encouraged a re-evaluation. METHODS: Three hundred ninety-six patients reducing triplets or twins were categorized as 3➔2, 3➔1, and 2➔1, Major (M) anomaly or minor (m) anomaly, same gender (SG), and those for whom gender preference (GP) was possible. Higher order and non chorionic villus sampling were excluded. FR decisions were prioritized by M anomaly, Suspicious, or m anomaly. If neither, we considered GP. RESULTS: Of 319, 214 (67%) had either M/m or SG. Of those, 3➔2 with gender option: 71/79 chose male and female or had no preferences, one chose male/male, and seven chose female/female. We reduced monochorionic twins in 33/35 3➔1 cases. Of 20 with GP choice, 10 chose male and 10 chose female. Of 162 2➔1, 54 had M or m, 50 were SG, but of the 44 M/F twins, 20 chose male and 24 chose female. CONCLUSIONS: There has been a cultural shift mostly preferring one of each or having no preference. When reducing to one, >50% prefer a girl. In addition to identifying abnormalities, chorionic villus sampling before FR expands patient autonomy.

Screening and testing in multiples.

The same principles for diagnosis and screening in singleton pregnancies apply to multiples. However, there can be significant differences in the safety and efficacy of all approaches with multiple gestations. This article deals with specific aspects of screening in multiple pregnancies.

Chorionic villus sampling and amniocentesis in 2008.

PURPOSE OF REVIEW: Over the past decades there have been wide discrepancies between quoted risks of diagnostic procedures (chorionic villus sampling and amniocentesis) yet little properly controlled and randomized data to back often dogmatic assertions. Here, we review the historical and current literature to determine realistic estimates. RECENT FINDINGS: Several papers this past year have addressed in cohort studies and meta-analyses composite risks for both chorionic villus sampling and amniocentesis. The studies have had varying degrees of reliability and likely reproducibility. SUMMARY: Despite one outlier paper, which had major methodological flaws, the consensus of the modern literature is that in experienced hands there is little to no differences between the procedure risks of amniocentesis and chorionic villus sampling. The latter, however, is clearly harder to learn and has a steeper learning curve.