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Objective We have previously demonstrated that maternal‐plasma cell‐free DNA (cfDNA)‐testing can detect chromosomal anomalies in recurrent pregnancy loss (RPL) with 81.8% sensitivity and 90.3% specificity. Here we assess whether this is cost effective in guiding further workup in RPLs. Method A decision‐analytic model was developed to compare the cost of various RPL management pathways: (1) current American Society for Reproductive Medicine (ASRM) RPL workup; (2) microarray or karyotyping analysis of products of conception (POCs) and RPL workup only for euploid cases; and (3) cfDNA testing and RPL workup only for euploid cases. Sample accessibility, failure rates, and sensitivity were specified for each test. Costs of sample collection, genetic tests, and RPL workup were considered. Analysis outcomes included detection rate of chromosomal anomaly and cost per patient tested. Results In comparison to existing cytogenetic testing on POCs, cfDNA testing pathway allowed for better sample accessibility with a lower cost per patient. In addition, using cfDNA to guide further workup significantly increases the number of causative fetal chromosome anomalies detected, reducing the number of patients undergoing unnecessary workup resulting in an overall cost savings. Conclusion Our study showed that inclusion of cfDNA testing is a cost‐effective approach to guide RPL workup., Key points What is already known about this topic? Chromosomal anomalies account for 50%–70% of early pregnancy loss (EPL) and even in recurrent pregnancy loss (RPL) random aneuploidy is the single most common etiology, accounting for >50% of cases.In a previous study we have shown that maternal‐plasma genome‐wide cell‐free DNA (cfDNA)‐based testing can reliably detect chromosomal anomalies in random EPL and RPL with a sensitivity of 81.8% and a specificity of 90.3%.We therefore suggested cfDNA‐based testing serve to guide further management in cases of RPL: if cfDNA in the second and subsequent RPL demonstrates aneuploidy, no further action is taken; if an unbalanced rearrangement is found, parental karyotyping is recommended; if no abnormality is detected, the recommended RPL workup is performed. What does this study add? In this study we demonstrate that using cfDNA to guide further workup in RPL is a cost‐effective approach.We share our algorithm to facilitate local cost‐effectiveness analysis based on prevailing billing schemes, either based on national health systems or private payor systems.

STUDY QUESTION Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)? SUMMARY ANSWER Genome-wide cfDNA testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management. WHAT IS KNOWN ALREADY Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing. STUDY DESIGN, SIZE, DURATION This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort. MAIN RESULTS AND THE ROLE OF CHANCE Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases. LIMITATIONS, REASONS FOR CAUTION Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases. WIDER IMPLICATIONS OF THE FINDINGS cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed. STUDY FUNDING/COMPETING INTEREST(S) Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina’s Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.

This research sought to understand IVF-physicians’ knowledge of, experience with, and attitudes toward fertility preservation for cancer patients. A 35-question, self-report survey request was emailed to IVF providers who were registered on the IVF-Worldwide.com network (3826 clinics). Physicians submitted responses on the IVF-Worldwide.com website. Survey results were reported as a proportion of the responding clinics. Survey responses were completed by 321 (8.4%) globally distributed IVF clinics, representing 299,800 IVF cycles. Of these clinics, 86.6% (278) performed fertility preservation, treating approximately 6300 patients annually. However, 18.4% of the centers reported that patients sought advice independently, without an oncologist’s referral. Ovarian tissue cryopreservation was performed by 37.7% of the clinics, yet 52.6% considered the procedure experimental. IVM was performed by 16.5% of responding clinics. A majority (63.6%) of the clinics selected treatment protocols based on each patient’s malignancy. Most respondents (76.3%) disagreed that fertility preservation was not yet successful enough to make it an available option. However, 44.2% believed that pregnancy rates following oocyte cryopreservation could not be determined because not enough oocyte cryopreservation patients had completed embryo transfer. Most clinics performed fertility preservation, tailoring protocols to each patient’s disease and condition. Almost 20% of patients sought advice independently, indicating that more effort is needed to encourage oncologists to refer patients. Most survey respondents believed that data was not yet available on either live birth outcomes or the best protocol for each disease. Therefore, long-term study must continue, with the establishment of interim milestones and an outcome-tracking registry.

To evaluate whether ethnicity affects the risk of full mutation expansion among females heterozygous for FMR1 premutation.Women who carry the FMR1 premutation alelle of Jewish origin who underwent fragile X prenatal diagnosis between 2011 and 2018 in two medical centers in Israel were included. The heterozygote women and fetuses were analyzed for the number of CGG repeats and AGG interruptions.Seven hundred sixty-six subjects were included. Parental ethnicity was fully concordant in 592 cases (Jewish, Ashkenazi, and non-Ashkenazi). Ashkenazi compared with non-Ashkenazi heterozygotes have a significantly higher mean number of CGG repeats (68 ± 8.7, 64 ± 6.4 respectively, P = 0.03) and a lower mean number of AGG interruptions (0.89 ± 0.83, 1.60 ± 1.18 respectively, p = 0.0001). Overall, 56/198 (28.2%) fetuses of Ashkenazi heterozygotes had an expansion to a full mutation compared with 6/98 among the non-Ashkenazi (6.1%) (p = 0.001). Multivariate analysis demonstrated that, in addition to CGG repeats and AGG interruptions (which contributed 68.3% of variance), ethnicity is an independent risk factor for a full mutation expansion (odds ratio [OR] = 2.04, p 0.001) and accounted for 9% of the variation of a full mutation expansion.Apart from significant differences regarding the number of CGG repeats and AGG interruptions between Ashkenazi and non-Ashkenazi heterozygotes, ethnicity independently affects the risk of a full mutation.

The aim of this study was to devise an evidence-based scoring system for prioritizing mosaic aneuploid embryos for transfer. A retrospective analysis was performed of all sequential cytogenetic and molecular results on chorionic villi samples (n = 72,472) and products of conception (n = 3806) analysed at a single centre. The likelihood that a mosaic aneuploidy detected in chorionic villi samples will involve the fetus, the incidence of clinically significant fetal uniparental disomy in the presence of a mosaic in chorionic villi and the chance of the mosaicism culminating in miscarriage were used to generate a scoring system for prioritizing mosaic aneuploid embryos detected by preimplantation genetic screening. A composite score was obtained for each individual mosaic aneuploidy after assignment of an individual risk score based on the incidence/likelihood of each adverse outcome. A final additional score was assigned to viable full or mosaic aneuploidies with a well-defined phenotype. The higher the composite score the lower the priority for embryo transfer. In conclusion, due to the paucity of prospective studies on the actual transfer of mosaic aneuploid embryos, we suggest using this evidence-based scoring system to provide a useful tool for clinicians, embryologists and patients.

Chromosomal aberrations are a common cause for miscarriage. The purpose of this study was to evaluate factors that influence the frequency of chromosomal abnormalities in miscarriages and provide clinicians with a guideline for management of such cases.The study included 170 women who experienced pregnancy loss between the 2004 and 2014. Cytogenetic analysis of products of conception (POC) was routinely performed.Successful cytogenetic analysis was achieved in 144 cases (84%). Of these, 78 cases (54%) had a chromosomal aberration. The incidence of chromosomal aberrations was not statistically significant among patients with 1, 2, 3, 4 or ≥5 previous miscarriages (33.3%, 57.4%, 48.6%, 65.2%, and 59.1%, respectively, p = 0.227). The F/M ratio was similar in normal and abnormal POC karyotypes (1.2:1 and 1.3:1, respectively, p = 0.7).Contrary to previous assumptions we did not find correlation between number of previous spontaneous miscarriages a women experienced and chromosomal aberration in her current miscarriage.

We describe a case of Beckwith-Wiedemann syndrome (BWS) demonstrating pre- and post-natal intra-familial variability. Our first encounter with the family occurred in the 1990s following the birth of 3 affected offspring. The first two pregnancies presented with exomphalos and elevated second trimester maternal serum alpha-fetoprotein (msAFP, 3.43 and 4.01 MOM, respectively) as well as elevated maternal human chorionic gonadotrophin (mhCG, 4.33 and 8.8 MOM, respectively). The diagnosis of BWS was confirmed postnatally in both cases. The third ongoing pregnancy presented only with elevated mhCG (7.09 MOM) and no malformation. Nonetheless BWS was suspected. The diagnosis was confirmed postnatally with clinical manifestations including macroglossia and cleft palate. Two affected female siblings were also diagnosed with Mullerian agenesis in adulthood. Suspecting a common genetic etiology, sequencing of the CDKN1C gene revealed a maternally inherited, likely pathogenic variant (NM_000076.2: c.367_385del; p.(Ala123Serfs*143)) causative of BWS. Chromosomal microarray and whole exome sequencing did not reveal any other pathogenic variant that would explain the Mullerian agenesis. One of the affected females underwent successful preimplantation genetic testing (PGT) with a surrogate and gave birth to a healthy female. To the best of our knowledge, this is the first report of Mullerian agenesis as a possible rare expansion of the BWS phenotype. In addition, this case highlights the potential role of abnormal second trimester biochemical markers (msAFP, mHCG) as possible indicators of BWS, especially in familial cases.

Cell-free DNA-based noninvasive prenatal testing (cfDNA) is a relatively new screening tool that analyzes cfDNA circulating in maternal plasma to screen for aneuploidies. Since its introduction, cfDNA has been rapidly adopted by health care providers (HCPs). This rapid adoption, as well as progressive developments in the technology, requires professional societies to continuously update their guidelines to indicate the broadening scope both in terms of test indications and patient populations for whom it has become the appropriate primary test. CfDNA testing, initially applied to high-risk patients, is now largely considered an option for all patients. For HCPs, the rapid introduction of cfDNA into clinical practice has come with the requirement to stay up-to-date and accurately informed. We performed a survey to understand the current practices and views of European HCPs on the use of cfDNA. European HCPs were surveyed on several topics such as familiarity with cfDNA-based noninvasive prenatal testing (NIPT), current usage, patient counseling, test menu expansion, and future perspectives. The results of this survey demonstrate increasing usage and awareness of cfDNA-based NIPT in five European countries (UK, France, Germany, Spain and Italy). Major barriers to implementation include cost and a lack of physician education on NIPT.

We describe our experience with whole-exome sequencing (WES) in fetuses with central nervous system (CNS) abnormalities following a normal chromosomal microarray result. During the study period (2014–2017) 7 cases (9 fetuses) with prenatally diagnosed CNS abnormality, whose chromosomal microarray analysis was negative, were offered whole-exome sequencing analysis. A pathogenic or a likely pathogenic variant was found in 5 cases including a previously described, likely pathogenic de novo TUBA1A variant (Case #1); a previously described homozygous VRK1 variant (Case #2); an X-linked ARX variant (Case #3); a likely pathogenic heterozygous variant in the TUBB3 gene (Case #5). Finally, in two fetuses of the same couple (Case #6), a compound heterozygous state was detected, consisting of the NPHP1 gene deletion and a sequence variant of uncertain significance. Two additional cases had normal WES results. Whole-exome sequencing may improve prenatal diagnosis in fetuses with CNS abnormalities.

Item does not contain fulltext Introduction: Our objective was to evaluate the incidence of chromosomal aberration (both microscopic and submicroscopic) and the clinical outcome of fetuses with isolated muscular ventricular septal defect (VSD). Material and methods: The study included 40 pregnant women whose fetuses were diagnosed with isolated muscular ventricular septal defect (mVSD). Of these, 30 patients underwent amniocentesis and 10 declined. All samples were tested by chromosomal microarray analysis (CMA). Of the 40 women in the study, 32 gave birth and the clinical outcome of the children was retrieved from the patients' medical records. Results: Of the 30 patients who underwent amniocentesis, one was detected with mosaic Klinefelter syndrome and one was detected with a pathogenic copy number variant unrelated to the VSD. Clinical follow-up was performed on 26 children after birth. The first postnatal echocardiography did not detect a VSD in 13 (50%) of the followed-up children. Spontaneous closure occurred in another eight (30.8%) children during the postnatal follow-up period. In only five children (19.2%) VSD was still detected by echocardiography after the first year of life. Discussion: Isolated muscular VSD diagnosed prenatally does not appear to be a significant risk factor for chromosomal abnormalities and has a favorable clinical outcome.

Background The study is aimed to describe a novel strategy that increases the accuracy and reliability of PGD in patients using sperm donation by pre-selecting the donor whose haplotype does not overlap the carrier’s one. Methods A panel of 4–9 informative polymorphic markers, flanking the mutation in carriers of autosomal dominant/X-linked disorders, was tested in DNA of sperm donors before PGD. Whenever the lengths of donors’ repeats overlapped those of the women, additional donors’ DNA samples were analyzed. The donor that demonstrated the minimal overlapping with the patient was selected for IVF. Results In 8 out of 17 carriers the markers of the initially chosen donors overlapped the patients’ alleles and 2–8 additional sperm donors for each patient were haplotyped. The selection of additional sperm donors increased the number of informative markers and reduced misdiagnosis risk from 6.00% ± 7.48 to 0.48% ±0.68. The PGD results were confirmed and no misdiagnosis was detected. Conclusions Our study demonstrates that pre-selecting a sperm donor whose haplotype has minimal overlapping with the female’s haplotype, is critical for reducing the misdiagnosis risk and ensuring a reliable PGD. This strategy may contribute to prevent the transmission of affected IVF-PGD embryos using a simple and economical procedure. Trial registration All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. DNA testing of donors was approved by the institutional Helsinki committee (registration number 319-08TLV, 2008). The present study was approved by the institutional Helsinki committee (registration number 0385-13TLV, 2013).

The objective of this study is to evaluate the incidence of chromosomal aberration (both microscopic and sub-microscopic) in fetuses with an aberrant right subclavian artery (ARSA) detected by ultrasonographic anomaly scan.The study included 62 pregnant women whose fetuses were diagnosed with ARSA who were referred for genetic counseling. Of these, 55 patients underwent amniocentesis and 7 declined invasive testing. All 55 amniocentesis samples were tested by standard G-banding and chromosomal microarray, except for 2 samples for which only karyotype and fluorescence in situ hybridization for 22q11.2 deletions were performed.Of the 55 women who underwent amniocentesis, 5 were detected with trisomy 21 (9.1%), all of whom had additional ultrasound findings. Among the 14 fetuses with ARSA and additional ultrasound findings, the incidence of trisomy 21 was 35.7%. In fetuses with isolated ARSA, no chromosomal aberrations were detected by standard cytogenetic analysis and only one (1.9%) deleterious copy number variants (CNV) was detected by chromosomal microarray.Aberrant right subclavian artery with additional ultrasound findings constitute a strong predictor for aneuploidy. However, when ARSA is found in isolation, it confers no increased risk for aneuploidy or pathogenic CNVs. © 2017 John WileySons, Ltd.

We respond to the comments made in the BBC commissioned article by Heneghan and colleagues and the Panorama programme by Deborah Cohen about pre-implantation genetic screening (PGS), which was among the three “add on” treatments highlighted in the programme and the 41 listed in the article.12 Currently an extensive evidence base supports the efficacy of PGS: more than 20 retrospective studies and four randomised controlled trials suggest that, if performed to a high standard, PGS can, and does, improve IVF success for some patient groups.34567 We accept, however, that all studies are open to criticism and thus support further investigations, randomised and retrospective. However, the programme, …

Embryonic mosaicism, the presence of more than one distinct cell line within an embryo, has recently become the focus of growing attention and controversy in the context of preimplantation genetic screening (PGS). To evaluate the extent of mosaic aneuploidy in clinical practice and to gain insight on the practices and views regarding this issue, we conducted a survey using a prospective, 20-item Web-based questionnaire with questions related to practices and views regarding mosaicism in PGS. A total of 102 in vitro fertilization (IVF) units from 32 countries that performed 108,900 IVF cycles annually responded to the survey. More than half responded that embryonic mosaic aneuploidy is reported by the laboratory, but 31.9% stated that samples are reported as euploid or aneuploid only. If mosaic aneuploidy is reported, 46% stated that it was present in ≤10% of the embryos. More than two-thirds were of the opinion that next-generation sequencing is required to reliably detect mosaicism. Among centers performing PGS, 47.9% consider embryonic mosaicism when detected in >20% of the cells, and nearly two-thirds believe that mosaic aneuploid embryos should be stored for potential therapeutic use after extensive and appropriate counseling. In summary, mosaicism has always existed in preimplantation embryos, and new technologies can now detect its presence with higher resolution. More studies are needed before definite conclusions can be drawn.

Background Chromosomal microarray analysis is standard of care in fetuses with malformations, detecting clinically significant copy number variants in 5–7% of cases over conventional karyotyping. However, it also detects variants of uncertain significance in 1.6–4.2% of the cases, some of which are low-penetrance neuro-susceptibility loci. The interpretation of these variants in pregnancy is particularly challenging because the significance is often unclear and the clinical implications may be difficult to predict. Objective The purpose of this study was to describe counseling dilemmas regarding low-penetrance neuro-susceptibility loci that are detected by prenatal chromosomal microarray analysis. Study Design During the study period (January 2014 to December 2015), 700 prenatal chromosomal microarray analyses were performed. Cases were categorized as “indicated” (n=375) if there were abnormal sonographic findings or suggestive medical history and “patient choice” (n=325) in the presence of a structurally normal fetus with no other particular indication. The laboratory reported on copy number variants ≥400 Kb in size in loci known to be associated with genetic syndromes and ≥1 Mb in other areas of genome. Results were classified as gross aneuploidy, copy number variants, and normal. Copy number variants were categorized according to the American College of Medical Genetics standards and guidelines: pathogenic, variants of uncertain significance, or benign. Variants of uncertain significance were further subdivided into categories of likely pathogenic, variants of uncertain significance with no subclassification, and likely benign. Statistical analysis was performed with the use of Chi square test and Fisher’s exact test to compare intergroup differences in incidence of the different result categories and demographic data. Results Patient choice cases became more prevalent with time (35.5% in the beginning of the study, compared with 48.4% at the end of the study period). Clinically significant copy number variants were found in 14 of 375 (3.7%) of indicated cases vs only 2 of 325 (0.6%) of patient choice cases (P=.009). All “likely benign” variants consisted of low-penetrance neuro-susceptibility loci. The incidence thereof was similar between the indicated and patient choice groups (3.7% vs 3.4%; P=.85). In the indicated group, some variants of uncertain significance may have contributed to the abnormal anatomic findings. Conversely, in the patient choice group, the finding of low-penetrance neuro-susceptibility loci was often unexpected and confounding for prospective parents. Conclusion Prenatal chromosomal microarray analysis added clinically significant information in both groups. However, it also detected low-penetrance neuro-susceptibility loci in approximately 3.5% of the cases. This fact should be conveyed during pretest counseling to allow patients to make informed choices, particularly when chromosomal microarray is to be performed for patient choice.

Background Current risk calculations for trisomy 21, which are based on multiples of median (MoM), do not take into account possible differences between euploid and trisomy 21 pregnancies that may develop with gestational age. In order to optimize the predictive value of screening tests, we calculated the ratio between maternal serum concentration of alpha-fetoprotein (AFP) and that of human chorionic gonadotropin (hCG) in euploid and in trisomy 21 pregnancies. Methods The medians of the concentration ratios, [AFP]/[hCG] at 16–21 weeks of gestation, were plotted as a function of gestational age for 307 cases of trisomy 21 and were compared with the medians of 30 549 normal karyotype cases. Results [AFP]/[hCG] ratio medians were independent of body weight and maternal age. There was a significant difference in the [AFP]/[hCG] ratio when comparing trisomy 21 and euploid pregnancies at each week. This difference became greater with advancing gestational age (P < 0.01). Conclusion There is a significant difference in ratios of [AFP]/[hCG] between euploid and trisomy 21 pregnancies, which may be used to improve detection rates of Down syndrome screening. Copyright © 2009 John Wiley & Sons, Ltd.

Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the 'Farabee' founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N- and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.

Fragile X syndrome is caused by a dynamic mutation in the FMR1 gene. Normal individuals have55 CGG repeats in the 5 untranslated region, premutation carriers have 55-200 repeats and a full mutation has200 repeats. Female carriers are at risk of having affected offspring. A multiplex nested polymerase chain reaction protocol is described for preimplantation genetic diagnosis (PGD) of fragile X syndrome with simultaneous amplification of the CGG-repeat region, the Sry gene and several flanking polymorphic markers. The amplification efficiency wasor =96% for all loci. The allele dropout rate in heterozygotic females was 9% for the FMR1 CGG-repeat region and 5-10% for the polymorphic markers. Amplification failure for Sry occurred in 5% of single leukocytes isolated from males. PGD was performed in six patients who underwent 15 cycles. Results were confirmed in all cases by amniocentesis or chorionic villous sampling. Five clinical pregnancies were obtained (31% per cycle), four of which resulted in a normal delivery and one miscarried. This technique is associated with high efficiency and accuracy and may be used in carriers of full mutations and unstable high-order premutations.

We evaluated the clinical utility of screening for mutations in 34 breast/ovarian cancer susceptibility genes in high-risk families in Israel. Participants were recruited from 12, 2012 to 6, 2015 from 8 medical centers. All participants had high breast/ovarian cancer risk based on personal and family history. Genotyping was performed with the InVitae™ platform. The study was approved by the ethics committees of the participating centers; all participants gave a written informed consent before entering the study. Overall, 282 individuals participated in the study: 149 (53 %) of Ashkenazi descent, 80 (28 %) Jewish non-Ashkenazi descent, 22 (8 %) of mixed Ashkenazi/non-Ashkenazi origin, 21 (7 %) were non-Jewish Caucasians, and the remaining patients (n = 10–3.5 %) were of Christian Arabs/Druze/unknown ethnicity. For breast cancer patients (n = 165), the median (range) age at diagnosis was 46 (22–90) years and for ovarian cancer (n = 15) 54 (38–69) years. Overall, 30 cases (10.6 %) were found to carry a pathogenic actionable mutation in the tested genes: 10 BRCA1 (3 non-founder mutations), 9 BRCA2 (8 non-founder mutations), and one each in the RAD51C and CHEK2 genes. Furthermore, actionable mutations were detected in 9 more cases in 4 additional genes (MSH2, RET, MSH6, and APC). No pathogenic mutations were detected in the other genotyped genes. In this high-risk population, 10.6 % harbored an actionable pathogenic mutation, including non-founder mutations in BRCA1/2 and in additional cancer susceptibility genes, suggesting that high-risk families should be genotyped and be assigned a genotype-based cancer risk.

Non-invasive prenatal testing (NIPT) using cell-free DNA in maternal blood is a relatively new screening modality for the common trisomies of chromosomes 21, 18 and 13 and sex chromosome aneuploidies. For some patients, however, results are not reported because of laboratory technical issues such as low fetal fraction and sequencing failures. In this review, the clinical implications of NIPT test failures are discussed.A Medline search was performed for all studies on NIPT that include1000 samples. The failure rates were assessed by technology.Methods based on massive parallel sequencing have been found to have the lowest failure rate (1.58%), while tests based on single-nucleotide polymorphism analysis have the highest failure rate (6.39%).Recent publications suggest that patients who receive a 'no call' result are at increased risk of aneuploidy. Some professional societies have therefore recommended that these patients undergo genetic counseling and be offered invasive diagnostic testing. NIPT technology that has a high failure rate may increase the false positive rates, decrease the positive predictive value, and increase the procedure-related pregnancy loss. © 2016 John WileySons, Ltd.

Noninvasive prenatal testing using cell-free DNA in maternal blood for trisomy 21 was introduced in 2011. This technology has continuously evolved with the addition of screening for trisomy 18 and trisomy 13 followed by the inclusion of sex chromosome aneuploidies. Expanded noninvasive prenatal test panels have recently become available, which enable screening for microdeletion syndromes such as the 22q11.2 deletion (associated with the velocardiofacial syndrome) and others. However, the performance data for these microdeletion syndromes are derived from a small number of samples, mostly generated in vitro. Rigorous performance evaluation, as was done at least for trisomy 21 testing using cell-free DNA analysis, is difficult to perform given the rarity of each condition. In addition, detection rates may vary considerably depending on deletion size. Importantly, positive predictive values (PPVs), strongly influenced by the low prevalence, are expected to be significantly lower than 10% for most conditions. Thus, screening in an average-risk population is likely to have many more false-positives than affected cases detected. Conversely, testing in a high-risk population such as fetuses with cardiac anomalies may have higher PPVs, but a negative result needs to be considered carefully as a result of uncertain information about detection rates and a significant residual risk for other copy number variants and single gene disorders. This article integrates current knowledge on cell-free DNA testing for microdeletions with the aim to assist clinicians and policymakers in designing optimal programs for screening in pregnancy.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with a carrier frequency of approximately 1 in 40. Approximately 95% of patients have homozygous deletions of exon 7 and/or 8 of the SMN1 gene. Carrier testing for SMA is relatively complex and requires quantitative polymerase chain reaction (PCR) of genomic DNA to determine SMN1 copy number. The purpose of this study was to assess the feasibility of carrier testing for SMA in males, by nested PCR analysis of SMN1 deletions in single sperm cells. A nested PCR method was developed to amplify SMN1 exon 7 in single cells. Restriction enzyme digestion with DraI was used to differentiate between the highly homologous SMN1 and SMN2 genes. Single sperm cells from five known SMA carriers and six noncarriers were analyzed. Among the five carriers, a total of 132 single sperm cells were analyzed and SMN1 exon 7 deletion was detected in 68 cells (51.5%). In contrast, among the six noncarriers, a total of 136 single sperm cells were analyzed. Of these, an apparent SMN1 exon 7 deletion was detected in four sperm cells. This was interpreted as an allele dropout (ADO) rate of 2.9%. We conclude that nested PCR of SMN1 exon 7 is an accurate and reproducible method for detection of SMA male carriers with a SMN1 deletion.

Objective Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia. Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute to the increased risk of preeclampsia that has been observed in these patients. Our objective was to characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies. Study design Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies were obtained from first and second trimester screening programs. We chose 17 cases of trisomy 13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included. Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic techniques were used, and the results are reported as median and ranges. Results In early pregnancy trisomy 13 cases and control samples, the median circulating soluble fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range, 0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were not significantly different than the control samples. Furthermore, the differences between trisomy 13 and control samples were more pronounced in the second trimester specimens than in the specimens from the first trimester. Conclusion These data suggest that alterations in circulating angiogenic factors may be involved intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures these factors longitudinally and correlates them with pregnancy outcomes is needed to further establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.

Objective: Canavan disease is an autosomal recessive disorder which is relatively common in Ashkenazi Jews. It is characterized by developmental delay, severe hypotonia and early death, and is caused by a deficiency of aspartoacylase which is encoded by the ASPA gene. In Ashkenazi Jews, one major mutation (E285A) and one minor mutation (Y231X) account for the majority of cases. The objective of this study was to develop a preimplantation genetic diagnosis (PGD) protocol for Canavan disease. Methods: Two carrier couples requested PGD for Canavan disease. In 1 couple each was a carrier of a different ASPA mutation (Y231X and E285A). In the other couple both were carriers of the minor mutation (Y231X). A single-cell duplex nested polymerase chain reaction (PCR) protocol was first developed on single leukocytes obtained from the known carrier parents. Following verification in single leukocytes, clinical PGD was offered to both couples. Results: We evaluated 115 single leukocytes from known carriers and found an allele drop out rate of 1.7% for the fragment harboring the Y231X mutation and 0% for the fragment harboring the E285A mutation. One cycle of PGD was performed in each family. In the first, 11 embryos were successfully analyzed and 4 were found to be affected. Two unaffected embryos were transferred, but no pregnancy resulted. In the other family, 4 embryos were analyzed, 1 was affected, 2 were heterozygotes and 1 was homozygous normal. Following transfer of 2 unaffected embryos, a singleton pregnancy resulted, currently ongoing at 18 weeks gestational age. Amniocentesis performed at 16 weeks confirmed the diagnosis. Conclusion: Reliable PGD for Canavan disease is possible using a single-cell nested PCR approach.

Objective: To generate nomograms for the sonographic measurement of the fetal philtrum and chin during pregnancy. Design: A prospective, cross-sectional study in normal singleton pregnancies. Subjects: One hundred and fifty-three fetuses between 13 and 42 weeks of gestation were studied. Methods: The philtrum was measured from the base of the columella to the upper lip. The chin was measured from the tip of the lower lip to the skin under the lower tip of the mandible. Predictive models were evaluated to generate graphic description of the 5th, 50th and 95th centiles for the fetal philtrum and chin. Results: Fetal philtrum length increased with gestational age. The regression equation for the philtrum length (y) according to gestational age in weeks (x) is best predicted by the S-curve (Gompertz) model, as described by the following equation: y = exp(a + b/x), where a = 2.778577, and b = –23.476723 (R2 = 85.3%, p < 0.0001). The fetal chin length increased with gestational age. The regression equation for the mean chin length (y) according to gestational age in weeks (x) is best predicted by the S-curve model as described in the following equation. y = exp(a + b/x), where a = 3.7922, b = –28.043, (R2 = 89.0%, p < 0.0001). Conclusions: The nomograms generated in this study for the fetal philtrum and chin during pregnancy can be used in confirming subjective impression of facial dysmorphism.

Chordoma is an uncommon malignant neoplasm derived from remnants of the embryonal notochord. The tumor arises in the sacrococcygeal region in most cases. Cytogenetic information on clival chordomas is scarce due to the low incidence of these tumors. In this study, we applied the G-banding and spectral karyotyping techniques to compare the karyotypes of three variants of clival chordoma: conventional, chondroid, and dedifferentiated. We describe a normal karyotype of a chondroid chordoma and a complex karyotype of a conventional chordoma involving chromosomes 1, 2, 3, 5, 8, 9, 11, 15, 19, 20, and X. The cytogenetic analysis of the dedifferentiated chordoma showed a polyploid complex karyotype of 71-123 chromosomes with double minutes that originated from chromosome 17.

To compare the efficacy of two commercially available in vitro fertilization (IVF) and embryo culture media systems: the glucose-free P1 Medium supplemented with 20% synthetic serum substitute (SSS) (Irvine Scientific), and the Cook IVF Medium (Cook, Australia).A prospective randomized study. Medical center-based IVF Unit affiliated to the Faculty of Medicine of Tel Aviv University. IVF patients were randomly assigned to either P1 Medium supplemented with 20% SSS (182 patients, 196 cycles) or Cook Medium (167 patients, 179 cycles).Fertilization rates were similar with both media (52.3 +/- 26.1 and 53.8 +/- 27.6, respectively). Likewise, no difference was found in morphological characteristics and grading of cultured embryos. However, a significantly higher proportion of the embryos incubated in the P1 Medium reached the four-cell stage on day 2 or the 6-cell stage on day 3 postfertilization, compared to those incubated in Cook Medium (54.3% vs. 41.9%, p0.0001). Clinical pregnancy and delivery rates were improved when oocytes and embryos were cultured in P1 Medium. Finally, Implantation rate was significantly higher in the P1 Medium Group (9.9% vs. 6%, respectively).Our results suggest that the P1 Medium may be associated with a higher embryo cleavage rate and improved implantation rates compared to the Cook IVF Medium.

Objective. To assess the feasibility of nuchal translucency in triplets compared with singletons. Methods. Nuchal translucency thickness as part of routine first-trimester screening in the general population was compared between 3128 singleton pregnancies and 51 triplets (153 fetuses). Crown-rump length was also noted. The 5th, 50th, and 95th percentiles were determined and compared between the 2 groups, and regression curves of nuchal translucency measurements plotted against crown-rump length were drawn. Results. The mean nuchal translucency thickness was 1.23 mm for singletons and triplets. The 5th and 95th percentiles were also the same between the 2 studied groups. The regression curves of 5th, 50th, and 95th percentiles of nuchal translucency plotted against crown-rump length of triplets and singletons overlapped. Conclusions. Nuchal translucency values and distribution are the same in triplets and singletons, validating the utility of the cutoff values.

Objectives: To determine the levels of first-trimester free β-human chorionic gonadotrophin (free βhCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT) in twin pregnancies. Methods: The study included 93 patients with twin pregnancy and 4,977 with singletons who underwent first-trimester testing using free βhCG, PAPP-A and NT at 10–13 weeks of gestational age. Results: In twin pregnancies, the maternal serum free βhCG level was 2.18 higher and the PAPP-A level was 2.38 higher than in singleton pregnancies. These marker levels were significantly higher than the expected 2.0 multiples of the median (MoM). In contrast, NT values did not differ between twins and singletons. Conclusion: These data may be used to establish first-trimester combined screening for twin pregnancies.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by hereditary sensory and autonomic neuropathies. Although extremely rare in most populations, FD is common among Ashkenazi Jews (AJ), with a calculated carrier frequency of 1 in 30, based on disease prevalence. The gene for FD was recently identified as IKBKAP. One major mutation (IVS2 + 6T --C) is responsible in99.5% of cases among AJ. The purpose of this study was to determine the actual frequency of FD carriers in the AJ population in Israel and to determine whether carriers are more frequent among a subpopulation of AJ from Poland. The study group included 1267 Jews of Ashkenazi origin who were referred for routine DNA screening tests. These included 1100 individuals who were full AJ and 167 who were part AJ. None had a family history of FD. Mutation analysis for (IVS2 + 6T --C) was performed by PCR amplification followed by restriction enzyme analysis. All positive cases were confirmed by DHPLC WAVE( trade mark ). Among the 1100 full AJ tested, 34 were found to be FD carriers (1:32). The incidence of mutation carriers was significantly higher in AJ of Polish descent (1:18) compared to AJ of non-Polish descent (1:99). Among the 167 individuals who were part AJ, there were 3 carriers (1:56). The incidence of FD among AJ, particularly those of Polish background, warrants population screening. Population screening may be performed by denaturing high-performance liquid chromatography.

Objective: Pregnant infertility patients are commonly old enough to be offered prenatal diagnosis. However, they may be reluctant to undergo an additional invasive procedure. We, therefore, sought to determine what demographic factors, including race and ethnic group, influenced patients’ decisions to undergo genetic testing in addition to multifetal pregnancy reduction (MFPR). Methods: We retrospectively reviewed MFPR patients from July 1997 to June 1999 at our institution. Invasive genetic testing was routinely discussed. Maternal age, race, ethnicity, religion, egg source for in vitro fertilization (IVF) patients, and the remaining fetuses following MFPR were analyzed for invasive genetic testing determinants and were compared to our experiences with genetic referents to us for singleton pregnancies. 132 consecutive patients, of whom 49 were ≧35 years, including 15 having IVF with donor eggs, were included. Results: Maternal age was the single most significant determinant of testing. In donor egg cases, donor age was significant. Ethnic background, previous children, and the remaining number of fetuses after MFPR were also significant determinants. Conclusion: MFPR patients share similar demographics to the advanced maternal age population. Despite the very stressful situations, our data suggest that maternal age, and therefore genetic risk, is the most important determinant of choosing whether or not to have testing. However, patients’ decisions are, to varying degrees, modified by religious and ethnic considerations.

Objective The prenatal detection of de novo extra structurally abnormal chromosomes (ESACs) presents a challenge because the associated risk for congenital anomaly ranges from 100% to practically none, depending on the chromosomal origin. Despite the use of standard cytogenetic techniques and even fluorescence in situ hybridization (FISH), the origin of some ESACs often remains elusive. Spectral karyotyping (SKY™) is a molecular cytogenetic technique based on the simultaneous analysis of all chromosomes using a unique probe mix that allows the rapid identification of all chromosomes in 24 colors. The purpose of this study was to evaluate the use of SKY in the characterization of prenatally diagnosed de novo ESACs. Methods This series includes five cases of de novo ESACs detected prenatally in routine amniocentesis samples performed for advanced maternal age. Cases of inherited ESACs or ESACs defined by standard cytogenetic techniques were excluded. Results SKY analysis yielded valuable information, particularly in cases of nonsatellited ESACs: a der(18) and a ring(Y). In a case of a unisatellited der(15), SKY corroborated data obtained by standard cytogenetic techniques and FISH. Finally, in two cases of small bisatellited chromosomes, SKY was noncontributory. Conclusions While SKY may be a valuable tool in some cases, especially nonsatellited and ring ESACs, it does have limitations and should be used judiciously in conjunction with other cytogenetic techniques. Copyright © 2003 John Wiley & Sons, Ltd.

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis.

OBJECTIVE: To determine the risk of thrombophilias in women with unexplained intrauterine fetal deaths (IUFD). METHODS: All women with IUFD at 27 weeks’ gestation or greater were initially assessed during a period of 26 months. Subjects with multiple pregnancies, congenital anomalies, intrauterine infection, chorioamnionitis, immune hydrops, diabetes mellitus, previous thromboembolism, and severe hypertensive disease were excluded. The remaining 40 women with unexplained IUFD (study group) were matched for age and ethnicity with 80 healthy women who had at least one normal pregnancy (control group). All participants were tested at least 2 months after delivery for mutations of factor V Leiden, prothrombin gene, methylenetetrahydrofolate reductase, and for deficiencies of protein S, protein C, and antithrombin III. They were also tested and found to be negative for anticardiolipin antibodies. RESULTS: The gestational age at delivery and birth weight were significantly lower in the study group. The prevalence of inherited thrombophilias was 42.5% in the study group compared with 15% in the control group (odds ratio 2.8, 95% confidence interval 1.5, 5.3, P = .001). The prothrombin mutation and protein S deficiency rates were significantly higher in the study group (odds ratio 2.3, 95% confidence interval 1.3, 4.0, and odds ratio 3.2, 95% confidence interval 2.4, 4.1, respectively). CONCLUSION: Third-trimester IUFD is significantly associated with thrombophilias. These findings suggest that thrombophilia work-ups should be part of IUFD investigations and may have therapeutic and prognostic implications in future pregnancies.

Objective: The purpose of this study was to evaluate whether abnormal levels of first trimester maternal serum free human chorionic gonadotropin (β-hCG) are predictive of adverse pregnancy outcomes. Methods: The study included 1,622 consecutive patients with singleton pregnancies who underwent first trimester Down syndrome screening using nuchal translucency, and maternal serum free β-hCG and pregnancy-associated plasma protein-A. Patients with fetal anomalies or chromosome aberrations were excluded from the study. The incidences of various adverse pregnancy outcomes were evaluated according to maternal serum free β-hCG levels. Outcome variables included spontaneous miscarriage, proteinuric and non-proteinuric pregnancy-induced hypertension, fetal growth restriction, intrauterine fetal demise, spontaneous preterm delivery, oligohydramnios and placental abruption. Results: No significant differences were noted between groups for any of the demographic variables. The only statistically significant result was an increase in the relative risk for spontaneous miscarriage (RR = 6.33) at free β-hCG Conclusion: Low free β-hCG is associated with a higher incidence of spontaneous miscarriage but is a poor predictor of other pregnancy complications.

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and adaptive regression with autistic features, loss of acquired skills, and stereotypic hand movements that almost exclusively affects females. It is an X-linked dominant disorder, with presumed lethality in males. Nonetheless, there are a few descriptions of males suspected of having Rett syndrome. With the recent discovery that the MECP2 gene is responsible for most cases of Rett syndrome, it is possible to molecularly assess cases of affected males by direct sequencing analysis. We describe an Israeli family consisting of a female having classic Rett syndrome and a male sibling with severe neonatal encephalopathy. Molecular analysis revealed that both sister and brother have the same MECP2 gene mutation; however, their mother does not. This case, as well as other published studies of males with MECP2 mutations, reveals that the clinical manifestations in viable males vary from neonates with severe encephalopathy to adults with mental retardation and demonstrate genotype-phenotype correlations. (J Child Neurol 2002;17:20-24).

Down syndrome screening programmes lead to the prenatal diagnosis of other chromosomal abnormalities, some of which would not be detected by the secondary use of cell-free (cf)DNA testing in screen positives. This study aims to assess the number of these incidental diagnoses.This study is a systematic review of the literature to identify large prospective screening studies that reported diagnoses other than trisomies 21 and 18.There were ten informative prospective studies in which a total of 1,500,999 women were screened, and there were 3689 aneuploidy cases detected in the screen positives. Trisomy 21 was estimated to comprise only 58% of detected aneuploidies, trisomies 21 and 18 comprised 72%, and the common trisomies - 21, 18 and 13 - comprised 76%. Common trisomies and sex chromosome abnormalities, now included in all commercial cfDNA tests, were estimated to comprise 87% of aneuploidies in the Down syndrome screen positives. All these proportions were higher for second trimester protocols compared with those carried out wholly or partly in the first trimester.Secondary use of cfDNA testing will lead to about one-fifth reduction in diagnoses, taking account of both undetectable aneuploidies and false-negatives. This loss might be overcome by contingent cfDNA testing.

Of all markers evaluated for first-trimester biochemical screening for Down syndrome (DS), PAPP-A and free beta-hCG emerged as the most predictive. The combined test uses these markers in conjunction with nuchal translucency measurements, and is estimated to achieve a DS detection rate of 80% to 85% at a 5% false-positive rate. The integrated test, combining first-trimester sonographic and biochemical markers with second-trimester markers, provides a single estimate of a patients DS risk, and may yield a DS detection rate of 94% at a 5% false-positive rate. The acceptability and feasibility of this test, however, remain to be proved.

Diagnosing retained products of conception in a woman presenting with postpartum or postabortion bleeding presents a clinical challenge. Although ultrasonographic examination may be potentially useful in detecting retained products of conception, its accuracy has not yet been established. Saline infusion sonohysterography is a simple ultrasonographic technique for enhanced transvaginal sonographic imaging of the endometrial cavity by the instillation of saline into the uterine cavity during ultrasonographic evaluation. This technique enhanced our ability to diagnose retained products of conception, and we describe our experience in evacuating them under sonographic guidance while performing saline infusion sonohysterography.

Objective: We evaluated the value of all 3 common biochemical serum markers, maternal serum α-fetoprotein, β-human chorionic gonadotropin, and unconjugated estriol, and combinations thereof as predictors of pregnancy outcome. Study Design: A total of 60,040 patients underwent maternal serum screening. All patients had maternal serum α-fetoprotein measurements; β-human chorionic gonadotropin was measured in 45,565 patients, and 24,504 patients had determination of all 3 markers, including unconjugated estriol. The incidences of various pregnancy outcomes were evaluated according to the serum marker levels by using clinically applied cutoff points. Results: In confirmation of previous observations, increased maternal serum α-fetoprotein levels (>2.5 multiples of the median) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, intrauterine growth restriction, intrauterine fetal death, oligohydramnios, and abruptio placentae. Increased β-human chorionic gonadotropin levels (>2.5 multiples of the median [MoM]) were significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, and intrauterine fetal death. Finally, decreased unconjugated estriol levels (

Objective: Multifetal pregnancy reduction has been shown to improve survival rates in high-order multifetal pregnancies (≥4). There is, however, some controversy as to whether multifetal pregnancy reduction improves pregnancy outcomes of triplets reduced to twins. The purpose of this study was to evaluate this issue by comparing outcomes of triplet gestations undergoing reduction to twins with outcomes of nonreduced twin gestations and expectantly managed triplet gestations. Study Design: The study included 143 triplet pregnancies that underwent reduction to twins over a 10-year period at a single center. These were compared with 12 nonreduced triplet pregnancies from the Wayne State University Perinatal Database and with 2 groups of twin pregnancies: 605 from the Wayne State University Perinatal Database and 207 from the Quest Diagnostics Database. Results: The miscarriage rate for expectantly managed triplets was 25%, compared with 6.2% for triplets reduced to twins. This rate was similar to the rates for both groups of nonreduced twins: 5.8% (Quest) and 6.3% (Wayne State University). Severe prematurity occurred in 25% of nonreduced triplets compared with 4.9% of twins after reduction. This rate was also similar to that of nonreduced twins: 7.7% (Quest) and 8.4% (Wayne State University). The mean gestational age at delivery for expectantly managed triplets (32.9 ± 4.7 weeks) was significantly shorter than for triplets reduced to twins (35.6 ± 3.1 weeks). By comparison, nonreduced twins had a mean gestational age at delivery of 35.8 ± 3.9 weeks for Quest and 34.4 ± 3.6 weeks for Wayne State University. Mean birth weights were significantly lower in expectantly managed triplets as compared with triplets undergoing reduction to twins (1636 ± 645 g vs 2381 ± 602 g, respectively). Nonreduced twins had a mean birth weight of 2254 ± 653 g for Quest and 2123 ± 634 g for Wayne State University. Pregnancy loss rates, mean length of gestation, and mean birth weight did not vary significantly between triplets who underwent reduction to twins and nonreduced twins. Conclusions: Reduction of triplets to twins significantly reduces the risk for prematurity and low birth weight and may also be associated with a reduction in overall pregnancy loss. This suggests that multifetal pregnancy reduction of triplets to twins is a medically justifiable procedure not only from an actuarial viewpoint but also from the ethical perspective of supporting patients' autonomy and respect for patients' individual circumstances. (Am J Obstet Gynecol 1999;180:1268-71.)

Nondisjunction associated with advanced maternal age, a well-established factor in the etiology of autosomal trisomy, should equally affect all chromosomes. In this study we evaluate the association of advanced maternal age with the occurrence of potentially viable autosomal trisomies (13, 18 and 21). 275 aneuploid pregnancies were ascertained prenatally and were grouped according to chromosome anomaly diagnosed. Mean maternal age was significantly younger (p = 0.009) in pregnancies affected by trisomy 13 than in pregnancies with trisomy 21. An intermediate mean maternal age was observed in pregnancies affected by trisomy 18. Our study shows a trend of the more severe, but potentially viable, autosomal trisomies to be diagnosed at younger maternal age. This may substantiate the ‘relaxed selection hypothesis’ proposed to explain the association of aneuploid conceptions with advanced maternal age.

Objectives: Maternal nutritional deficiency is an important predisposing factor to congenital neural tube defects (NTDs). It was hypothesized that obese women may have an increased risk for NTDs. The aim of the present study was to address this question in a large cohort. Methods: A total of 72,915 consecutive cases of biochemical screening that had documented maternal weights and pregnancy outcomes were identified from the Quest Diagnostic Laboratories database. Patients were divided into five ranges of maternal weights, and the incidence of NTDs was calculated for each group. Based on the different definitions of maternal overweight, the data were also analyzed based on 2 groups only, obese and nonobese, using three cutoff points. Results: Seventy-nine pregnancies were complicated by NTDs (incidence of 1.08 per 1,000 pregnancies). Differences between maternal weights ranges were not found to be statistically significant (χ2 = 5.997, p = 0.19, power = 0.99). Differences between obese and nonobese mothers were not found to be statistically significant for all three analyses as well. Conclusions: Our present results do not support an association between maternal obesity and NTDs.

Selective termination is employed in multifetal pregnancies, in the presence of an abnormal fetus, in order to improve the prognosis of the normal fetuses. The term elective reduction is used to describe reduction in twin pregnancies for maternal medical conditions, psychological, or socioeconomic reasons. The purpose of this study was to evaluate the factors that influence outcome in such pregnancies. Eighty-two twin pregnancies underwent selective termination (n = 59) or elective reduction (n = 23) over a 10-year period. Early procedures, performedor = 14 weeks (n = 31), had a pregnancy loss of 9.7% and a mean procedure-to-loss interval of 4.1 +/- 2.8 weeks; mean birthweight was 3299 +/- 395 g in survivors, with a mean gestational age at delivery of 38.4 +/- 2.3 weeks. In comparison, procedures performed14 weeks (n = 51) had a pregnancy loss of 7.8%, with a procedure-to-loss interval of 1.2 +/- 0.6 weeks. Mean birthweight was 2577 +/- 999 g, with a mean gestational age at delivery of 35.7 +/- 5 weeks. In conclusion, outcomes were more favourable among patients who underwent a first trimester procedure. The slight increase in pregnancy loss may be attributed to a higher than expected rate of spontaneous abortions in the first trimester, as manifested by the higher procedure-to-loss interval after a first trimester procedure. These facts underscore the importance of early detection of fetal abnormalities in twin pregnancies by ultrasonography and chorionic villus sampling.

Objective: To identify determinants of requesting pastoral care (PC) at the time of pregnancy termination for fetal anomalies. Methods: PC was provided by a hospital-based chaplain. Data were reviewed for 88 women who elected pregnancy termination. Nominal logistic regression and Kruskal-Wallis and Student t tests were used as appropriate. Results: None of 37 women who underwent dilatation and curettage (D&C) or dilatation and evacuation (D&E) requested PC as compared with 40 of 51 patients who underwent prostaglandin induction of labor (p < 0.001). The decision to seek PC was related to gestational age (p < 0.001), but not to maternal age, prior termination of pregnancy, gravidity, parity, racial background, or insurance status. The gestational age was also a significant predictor of the procedure performed (p < 0.001). D&C/D&E were significantly more likely to be performed at earlier gestational ages. Women seeking PC were less likely to have experienced previous pregnancy loss or the death of a child. Among women who sought PC, 20% had experienced previous pregnancy loss or the death of a child, as opposed to 54% of women in the prostaglandin group who did not seek PC (p = 0.03). In the D&C/D&E group, the figure was 46%. Conclusions:Utilization of PC is much more frequent among women undergoing prostaglandin induction of labor than D&C/D&E. Determinants of seeking PC are related to issues congruent with choices of the termination procedure. Patients who experienced a previous pregnancy loss or the death of a child are also less likely to feel the need, or do not want, chaplaincy involvement.