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1.  [No title available] 
PMCID: PMC3999234  PMID: 24190763
2.  Discovery of Epigenetic Biomarkers for the Non-Invasive Diagnosis of Fetal Disease 
Prenatal diagnosis  2012;32(6):542-549.
The primary goal of this study was to identify CpG sites in the human genome that are differentially methylated in DNA obtained from chorionic villus samples (CVS) and gestational age-matched maternal blood cell (MBC) samples.
We used the HumanMethylation27 DNA Analysis BeadChip to characterize DNA methylation in samples of CVS and MBC. We then selected a subset of differentially methylated CpG sites on chromsome 13 and subjected them to analysis by mass spectrometry using the Epityper platform.
We identified 718 tissue-specific differentially methylated regions (DMRs) between MBC and CVS. 563 of these were hypermethylated in MBC and hypomethylated in CVS whereas 155 sites were hypomethylated in MBC and hypermethylated in CVS. Further analysis of 13 DMRs on chromosome 13 by Epityper confirmed the microarray data and provided us with additional data about the methylation patterns of surrounding CpG sites.
Analysis of the resulting data identified a large number of CpGs that are potential biomarkers for the selective amplification of fetal DNA from maternal plasma and the subsequent non-invasive detection of trisomy 13.
PMCID: PMC4308692  PMID: 22495992
Fetal; DNA; Plasma; DNA Methylation; Aneuploidy; NIPD
3.  [No title available] 
PMCID: PMC4293073  PMID: 19382114
4.  Integration Of Microarray Technology Into Prenatal Diagnosis: Counseling Issues Generated During The NICHD Clinical Trial 
Prenatal diagnosis  2012;32(4):396-400.
Cytogenetic microarray analysis (CMA) in prenatal testing detects chromosome abnormalities and new genetic syndromes that would be missed by conventional cytogenetics and has the potential to significantly enhance prenatal genetic evaluation. A large NICHD-sponsored multi-centered trial to assess the role of CMA as a primary prenatal diagnostic tool has been completed, and results will soon be available. Integration of this technology into clinical care will require thoughtful changes in patient counseling. Here we examine four cases, all ascertained in the NICHD prenatal microarray study, to illustrate the challenges and subtleties of genetic counseling required with prenatal CMA testing. While the specifics of each case are distinct, the underlying genetic principles of uncertainty, variable expressivity, and lack of precise genotype-phenotype correlation are well known and already part of prenatal counseling. Counselor and practitioner education will need to include both the science of interpreting array findings as well as development of improved approaches to uncertainty. A team approach to interpretation will need to be developed, as will standardized guidelines by professional organizations and laboratories. Of equal import is additional research into patient attitudes and desires, and a better understanding of the full phenotypic spectrum of copy number variants discovered in-utero.
PMCID: PMC4251739  PMID: 22467170
5.  No evidence for mutations in NLRP7 and KHDC3L in women with androgenetic hydatidiform moles 
Prenatal diagnosis  2013;33(13):1242-1247.
To evaluate the mutational spectrum of NLRP7 and KHDC3L (C6orf221) in women with sporadic and recurrent androgenetic complete hydatidiform moles (AnCHM) and biparental hydatidiform moles (BiHM) to address the hypothesis that autosomal recessive mutations in these genes are only or primarily associated with biparental hydatidiform moles.
We recruited 16 women with suspected recurrent and sporadic AnCHM and 5 women with suspected BiHM in addition to their reproductive partners into our study. We then sequenced the coding exons of NLRP7 and KHDC3L from DNA isolated from either blood or saliva from the study subjects.
Sequence analysis of NLRP7 and KHDC3L revealed previously described SNPs in patients with AnCHM. However in patients with BiHM, we identified a novel homozygous mutation and a previously described intragenic duplication of exon 2-5 in NLRP7, both of which are likely to be disease causing. We did not identify mutations in KHDC3L in patients with the either forms of HM.
The absence of mutations in the women with AnCHM supports a role of NLRP7 or KHDC3L in BiHM only. The absence of mutations in KHDC3L in women with BiHM is consistent with its minor role in this disease compared to NLRP7, the major BiHM gene.
PMCID: PMC3951116  PMID: 24105752
6.  Fetal diagnostic indications for second and third trimester outpatient pregnancy termination 
Prenatal Diagnosis  2014;34(5):438-444.
To determine the frequency of diagnostic indications among women seeking to terminate pregnancies for reasons of fetal abnormality, spontaneous fetal demise, or a genetic disorder in a private outpatient clinic specializing in late outpatient abortion procedures.
A total of 1005 women requested termination of pregnancy for reasons of genetic disorder, fetal anomaly, or fetal demise over 20 years (1992–2012). Gestational ages ranged from 12 to 39 weeks. In all cases, a documented diagnosis of fetal abnormality or fetal demise was made prior to referral. Records were reviewed to verify fetal diagnosis for all patients seeking termination of pregnancy for reasons of fetal disorder. Major complications included major unintended surgery, hemorrhage requiring transfusion, or pelvic infection.
Preoperative diagnoses included the following: chromosomal abnormalities (n = 378), genetic syndromes and single gene disorders (n = 30), structural anomalies (n = 494), and other conditions (n = 103). These include 26 cases of spontaneous fetal demise and nine selective terminations of one abnormal twin. The major complication rate was 0.5%.
The majority of diagnoses were in the categories of genetic disorder and neurologic abnormality. © 2014 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.
PMCID: PMC4238813  PMID: 24424620
8.  Global gene expression analysis of amniotic fluid cell-free RNA from recipient twins with twin-twin transfusion syndrome 
Prenatal diagnosis  2013;33(9):873-883.
To understand the biological pathways involved in twin-twin transfusion syndrome (TTTS) by performing global gene expression analysis of amniotic fluid (AF) cell-free RNA.
Prospective whole transcriptome microarray study analyzing cell-free RNA in AF from TTTS recipient twins and singleton controls. Significantly differentially-regulated genes in TTTS cases (N= 8) vs. matched controls (N = 8) were identified and pathways analyses performed. Significant gene expression differences between Stage II TTTS recipients (N = 5) and Stage III TTTS recipients with abnormal Doppler measurements (N = 5) were also analysed.
Analysis of paired data from TTTS cases and controls revealed differential expression of 801 genes, which were significantly enriched for neurological disease and cardiovascular system pathways. We also identified cardiovascular genes and pathways associated with the presence of critically abnormal Doppler measurements in Stage III TTTS recipients.
This study provides the first transcriptome-wide data on the impact of TTTS on fetal development. Our results show that gene expression involving neurological and cardiovascular pathways are altered in recipient fetuses prior to surgical treatment. This has relevance for the origins of long-term complications seen in survivors and for the development of future fetal biomarkers.
PMCID: PMC3773178  PMID: 23640821
9.  SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy 
Prenatal diagnosis  2013;33(7):643-649.
To develop a single nucleotide polymorphism- and informatics-based non-invasive prenatal test that detects sex chromosome aneuploidies early in pregnancy.
Fifteen aneuploid samples, including thirteen 45,X, two 47,XXY, and one 47,XYY, along with 185 euploid controls, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex PCR assay that targeted 19,488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y, and sequenced. Sequencing results were analyzed using a Bayesian-based maximum likelihood statistical method to determine copy number of interrogated chromosomes, calculating sample-specific accuracies.
Of the samples that passed a stringent quality control metric (93%), the algorithm correctly identified copy number at all five chromosomes in all 187 samples, for 934/935 correct calls as early as 9.4 weeks of gestation. We detected 45,X with 91.7% sensitivity (CI: 61.5-99.8%) and 100% specificity (CI: 97.9-100%), and 47,XXY and 47,XYY. The average calculated accuracy was 99.78%.
This method non-invasively detected 45,X, 47,XXY, and 47,XYY fetuses from cfDNA isolated from maternal plasma with high calculated accuracies, and thus offers a non-invasive method with the potential to function as a routine screen allowing for early prenatal detection of rarely diagnosed yet commonly occurring sex aneuploidies.
PMCID: PMC3764608  PMID: 23712453
10.  Best Ethical Practices for Clinicians and Laboratories in the Provision of Non-Invasive Prenatal Testing 
Prenatal diagnosis  2013;33(7):656-661.
To provide an ethical framework for clinicians and companies providing non-invasive prenatal testing using cell-free fetal DNA or whole fetal cells.
In collaboration with an NIH-supported research ethics consultation committee, together with feedback from an inter-disciplinary group of clinicians, members of industry, legal experts and genetic counselors we developed a set of best practices for the provision of non-invasive prenatal genetic testing.
Principal recommendations include the amendment of current informed consent procedures to include attention to the non-invasive nature of new testing and the potential for a broader range of results earlier in the pregnancy. We strongly recommend that tests should only be provided through licensed medical providers and not direct-to-consumer.
Prenatal tests, including new methods using cell-free fetal DNA, are not currently regulated by government agencies and limited professional guidance is available. In the absence of regulation, companies and clinicians should cooperate to adopt responsible best ethical practices in the provision of these tests.
PMCID: PMC4057377  PMID: 23613322
11.  Commercial Landscape of noninvasive prenatal testing in the United States 
Prenatal diagnosis  2013;33(6):521-531.
Cell-free fetal DNA-based noninvasive prenatal testing (NIPT) could significantly change the paradigm of prenatal testing and screening. Intellectual property (IP) and commercialization promise to be important components of the emerging debate about clinical implementation of these technologies. We have assembled information about types of testing, prices, turnaround times and reimbursement of recently launched commercial tests in the United States from the trade press, news articles, and scientific, legal, and business publications. We also describe the patenting and licensing landscape of technologies underlying these tests and ongoing patent litigation in the United States. Finally, we discuss how IP issues may affect clinical translation of NIPT and their potential implications for stakeholders. Fetal medicine professionals (clinicians and researchers), genetic counselors, insurers, regulators, test developers and patients may be able to use this information to make informed decisions about clinical implementation of current and emerging noninvasive prenatal tests.
PMCID: PMC3898859  PMID: 23686656
12.  The Incidence of Isolated Single Umbilical Artery in Twins And Adverse Pregnancy Outcomes 
Prenatal diagnosis  2013;33(3):269-272.
To estimate the incidence of single umbilical artery (SUA) in twin pregnancies and to investigate whether SUA in twin gestations is associated with adverse obstetric outcomes.
Retrospective cohort study of consecutive twin pregnancies over 17 years at a tertiary care hospital. Primary exposure was SUA in one or both twins documented at routine second trimester anatomic survey. Adverse obstetric outcomes included small for gestational age (SGA), placental abruption, and preterm birth, evaluated in univariable and multivariable analyses. Analysis was performed both at the pregnancy level and at the fetal level using paired analyses to account for the non-independence of twin pairs.
Of 2,378 twin pregnancies without major anatomic abnormalities, 1.7% (n=40) had SUA. Only 1 pregnancy (one monochorionic twin pair) was complicated by both twins having SUA. Twin fetuses with SUA are at increased risk for SGA (aOR 2.1 (1.2-4.1), p=0.03) after adjusting for pertinent confounding factors, similar to the findings of previous studies in singleton pregnancies. In addition, twins with SUA may be at increased risk for preterm delivery before 28 weeks compared to twin pregnancies with normal three-vessel umbilical cords (aOR 3.2 (1.3-7.89.4), p=0.01).
The incidence of SUA in twin gestations in this cohort is significantly less than recently published data. Similar to reports in singleton gestations, SUA appears to be associated with an increased risk for SGA in twins.
PMCID: PMC3612977  PMID: 23354986
Twin pregnancies; Single Umbilical Artery; Fetal anomaly
13.  Doppler fetal mechanical PR interval prolongation with positive maternal anti-RNP but negative SSA/Ro and SSB/La auto-antibodies 
Prenatal diagnosis  2010;30(8):797-799.
PMCID: PMC3904229  PMID: 20582918
fetal atrio-ventriculat block; fetal Doppler; PR interval; systemic lupus erythematosus
14.  Non-invasive prenatal aneuploidy testing at chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci 
Prenatal diagnosis  2012;32(13):1233-1241.
Develop a non-invasive prenatal test based on analysis of cell-free DNA in maternal blood to detect fetal aneuploidy at chromosomes 13, 18, 21, X, and Y.
166 samples from pregnant women, including eleven trisomy 21, three trisomy 18, two trisomy 13, two 45,X, and two 47,XXY samples were analyzed using an informatics-based method. Cell-free DNA from maternal blood was isolated and amplified using a multiplex PCR assay targeting 11,000 SNPs on chromosomes 13, 18, 21, X, and Y in a single reaction, then sequenced. A Bayesian-based Maximum Likelihood statistical method was applied to determine the chromosomal count of the five chromosomes interrogated in each sample, along with a sample-specific calculated accuracy for each test result.
The algorithm correctly reported the chromosome copy number at all five chromosomes in 145 samples that passed a DNA quality test, for a total of 725/725 correct calls. The average calculated accuracy for these samples was 99.92%. Twenty-one samples did not pass the DNA quality test.
This informatics-based method non-invasively detected fetuses with trisomy 13, 18, and 21, 45,X, and 47,XXY with high sample-specific calculated accuracies for each individual chromosome and across all five chromosomes.
PMCID: PMC3548605  PMID: 23108718
15.  Noninvasive fetal genome sequencing: a primer 
Prenatal diagnosis  2013;33(6):547-554.
We recently demonstrated whole genome sequencing of a human fetus using only parental DNA samples and plasma from the pregnant mother. This proof-of-concept study demonstrated how samples obtained noninvasively in the first or second trimester can be analyzed to yield a highly accurate and substantially complete genetic profile of the fetus, including both inherited and de novo variation. Here, we revisit our original study from a clinical standpoint, provide an overview of the scientific approach, and describe opportunities and challenges along the path towards clinical adoption of noninvasive fetal whole genome sequencing (NIFWGS).
PMCID: PMC3727971  PMID: 23553552
16.  Using FISH to increase the yield and accuracy of karyotypes from spontaneous abortion specimens 
Prenatal diagnosis  2011;31(8):755-759.
Cytogenetic analysis of spontaneous abortions is frequently complicated by culture failure and maternal cell contamination. The objective of the study is to demonstrate that multiplex FISH can increase the yield and accuracy of karyotypes from spontaneous abortion specimens.
A multiplex interphase FISH probe set was used to analyze two sample sets: First, uncultured tissues from 153 abortions samples with a normal 46,XX karyotype; and Second, a series of 171 samples that either failed to grow or were contaminated. Maternal cell contamination (MCC) studies were performed on 70 cultures where both karyotype and FISH indicated a normal female karyotype.
FISH showed 31% (53/171) of the specimens karyotyped as 46,XX were either male or abnormal. 23% (40/118) of these specimens were found to have an abnormal chromosome complement. In specimens with culture failure, FISH showed an abnormal complement in 44.4% (68/153). MCC studies showed 41.49% (29/70) cultures of maternal origin, 45.7% (32/70) fetal, 11.4% (8/70) a maternal/fetal mixture and 1 diploid mole.
Results demonstrate the utility of a simple FISH panel in increasing the detection rate of abnormal karyotypes. They also reveal the high frequency of overgrowth of maternal cells in cultured specimens from villi after embryonic loss.
PMCID: PMC3791617  PMID: 21484844
17.  First-Trimester Prediction of Preterm Birth Using ADAM12, PAPP-A, Uterine Artery Doppler and Maternal Characteristics 
Prenatal diagnosis  2012;32(10):1002-1007.
To estimate the efficiency of first-trimester ADAM12, PAPP-A, uterine artery Doppler and maternal characteristics in the prediction of preterm birth (PTB).
A prospective cohort study of patients presenting for first-trimester aneuploidy screening. Maternal serum ADAM12 and PAPP-A levels were measured by immunoassay, and mean uterine artery Doppler pulsatility indices were calculated. The primary outcome was preterm birth (PTB) <34 weeks’ gestation, and the secondary outcome was PTB <37 weeks’ gestation. Logistic regression was used to model the prediction of PTB using ADAM12, PAPP-A, uterine artery Doppler, and maternal characteristics, individually and in combination. Sensitivity, specificity, and area under the receiver-operating characteristic curves were compared between models.
Of 578 patients, 36 (6.2%) delivered <34 weeks and 78 (13.5%) delivered <37 weeks. For a 20% fixed false positive rate, ADAM12, PAPP-A, and uterine artery Doppler identified 58%, 52%, and 62% of patients with PTB <34 weeks and 42%, 48%, and 50% of patients with PTB <37 weeks, respectively. Combining these first-trimester parameters did not improve the predictive efficiency of the models.
First-trimester ADAM12, PAPP-A, and uterine artery Doppler are each modestly predictive of PTB; however, combinations of these parameters do not further improve their screening efficiency.
PMCID: PMC3463727  PMID: 22847849
ADAM12; PAPP-A; preterm birth; uterine artery Doppler
19.  First-trimester prediction of Preeclampsia using metabolomic biomarkers: a discovery phase study 
Prenatal diagnosis  2011;31(10):990-994.
We tested the hypothesis that first-trimester metabolic biomarkers offered a unique profile in women with preeclampsia (PE) in the second half of pregnancy, compared to controls.
We conducted a nested-case control study within a prospective cohort of pregnant women followed from the first-trimester to delivery. Cases were those who developed PEat any gestational age and these were compared with a control group without adverse pregnancy outcome, matched for gestational age within three days. We analyzed maternal blood obtained at 11–14 weeks’ gestation for 40 acylcarnitine species (C2-C18 saturated, unsaturated, and hydroxylated) and 32 amino acids by LC tandem mass spectrometry. Logistic regression modeling estimated the association of each metabolite with development ofPE.
We compared 41 cases with preeclampsia with 41 controls, and found four metabolites (Hydroxyhexanoylcarnitine, alanine, phenylalanine, and glutamate) that were significantly higher in the cases withPE. The area under the curve (AUC) using these metabolites individually to predict PE varied from 0.77–0.80; and when combined, the AUC improved to 0.82(95% CI 0.80–0.85) for all cases of PEand 0.85 (95% CI 0.76–0.91) for early onsetPE.
Our findings suggest a potential role for first-trimester metabolomics in screening for PE.
PMCID: PMC3713070  PMID: 21744367
20.  Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases† 
Prenatal diagnosis  2009;29(1):29-39.
To evaluate the use of array comparative genomic hybridization (aCGH) for prenatal diagnosis, including assessment of variants of uncertain significance, and the ability to detect abnormalities not detected by karyotype, and vice versa.
Women undergoing amniocentesis or chorionic villus sampling (CVS) for karyotype were offered aCGH analysis using a targeted microarray. Parental samples were obtained concurrently to exclude maternal cell contamination and determine if copy number variants (CNVs) were de novo, or inherited prior to issuing a report.
We analyzed 300 samples, most were amniotic fluid (82%) and CVS (17%). The most common indications were advanced maternal age (N = 123) and abnormal ultrasound findings (N = 84). We detected 58 CNVs (19.3%). Of these, 40 (13.3%) were interpreted as likely benign, 15 (5.0%) were of defined pathological significance, while 3 (1.0%) were of uncertain clinical significance. For seven (~2.3% or 1/43), aCGH contributed important new information. For two of these (1% or ~1/150), the abnormality would not have been detected without aCGH analysis.
Although aCGH-detected benign inherited variants in 13.3% of cases, these did not present major counseling difficulties, and the procedure is an improved diagnostic tool for prenatal detection of chromosomal abnormalities.
PMCID: PMC3665952  PMID: 19012303
aCGH; chromosomal abnormality; chromosomal microarray analysis; prenatal; copy number variants; CVS; amniotic fluid
21.  Amniocentesis in twin pregnancies: A systematic review of the literature 
Prenatal Diagnosis  2011;32(5):409-416.
Using published data, we sought to determine the amniocentesis-related loss rate in twin gestations.
We searched the PUBMED database using keywords “amniocentesis”, “twin” and “twins” to identify articles evaluating genetic amniocentesis in twin gestations published from January 1970 to December 2010. Random effects models were used to pool procedure-related loss rates from included studies.
The definition of “loss” varied across the 17 studies identified (Table 1). The pooled procedure-related loss rate at < 24 weeks was 3.5% (95% confidence interval [CI] 2.6-4.7) (Figure 2). Pooled loss rates at < 28 weeks (Figure 4) and to term (Figure 5) could not be calculated due to unacceptable heterogeneity of available data. Seven studies included a control (no amniocentesis) group and reported a pooled odds ratio for total pregnancy loss among cases of 1.8 (95% CI 1.2-2.7) (Figure 3). Only 1 study reported procedure-related loss rates by chorionicity (7.7% among monochorionics vs 1.4% among controls; p 0.02).
Analysis of published data demonstrated a pooled amniocentesis-related loss rate of 3.5% in twin gestations < 24 weeks. Pooled loss rates within other post-amniocentesis intervals or other gestational age windows and the impact of chorionicity on procedure-related loss rates cannot be determined from published data.
PMCID: PMC3330135  PMID: 22028248
twin; amniocentesis; loss rate
22.  Prenatal Diagnosis of Atrial Restriction in Hypoplastic Left Heart Syndrome is Associated with Decreased 2-Year Survival 
Prenatal Diagnosis  2012;32(5):485-490.
To compare the course of HLHS patients diagnosed prenatally with any degree of atrial restriction with those without evidence of atrial restriction.
Retrospective, cohort.
Prenatally diagnosed HLHS patients from 8/1999–1/2009 were categorized as non-restrictive versus restrictive, defined by left atrial hypertension on pulmonary venous Doppler and/or an interatrial septum.
Of 73 total fetal patients identified, 49 were liveborn. Survival at 2 years was 29/35 (83% CI: 59.5%–88.9%) for the non-restrictive group and 6/14 (43% CI:17.7%–66.0%) for the restrictive group (p<0.0001). Of those who underwent stage 1 palliation (35 with nonrestrictive and 10 with restrictive atrial septa) both groups had a similar incidence of preoperative acidosis and need for ventilation and inotropic support. Postoperatively, there was no difference between groups in ventilator days, length of stay, or survival to discharge. There was decreased survival at 2 years in the restrictive group, 60% (CI: 26.2%–87.8%) versus 83% (CI: 66.4%–93.4%) in the non-restrictive group. Furthermore, a disproportionate number of interstage deaths was evident in the restrictive group.
Prenatal presence of any degree of atrial septal restriction in the setting of HLHS confers a significant survival disadvantage, with increases in both early and late mortality.
PMCID: PMC3348961  PMID: 22511219
23.  Noninvasive Prenatal Diagnosis: Pregnant Women’s Interest and Expected Uptake 
Prenatal diagnosis  2011;31(13):1292-1299.
To investigate pregnant women’s level of future interest in noninvasive prenatal diagnosis (NIPD) and what factors might affect expected uptake of this testing.
Written questionnaires were administered to women in their third trimester.
One hundred fourteen women returned the questionnaire (80.9% response rate). Of these, 71.9% reported interest in NIPD, 22.7% were ambivalent and 5.4% were uninterested. Safety of the fetus was the single most important factor in 75% of women’s decisions. Factors associated with increased interest in NIPD included: older age (p=0.036), higher education (p=0.013), Caucasian or Asian ethnicity (p=0.011), and higher likelihood to terminate an affected pregnancy (p=0.002). Nearly 20% of women reported that they would do whatever their doctor recommended regarding NIPD, and 94.4% of women wished to meet with a genetic counselor at some point to discuss NIPD.
The majority of pregnant women report hypothetical interest in NIPD, primarily due to increased safety for the fetus, although a significant minority are uninterested or ambivalent. Discussions with healthcare providers regarding NIPD, and their recommendations, are likely to be an important factor in women’s decisions about this testing. As such, adequate discussion of the implications of prenatal diagnostic testing will be critical.
PMCID: PMC3225485  PMID: 22028097
prenatal testing; noninvasive prenatal diagnosis; prenatal screening; chromosome abnormalities; patient decision-making
24.  Cell-free fetal DNA testing: A pilot study of obstetric healthcare provider attitudes towards clinical implementation 
Prenatal diagnosis  2011;31(11):1070-1076.
To provide a preliminary assessment of obstetric healthcare provider opinions surrounding implementation of cell-free fetal DNA testing.
A 37-question pilot survey was used to address questions around the translation and use of non-invasive prenatal testing using cell-free fetal DNA. The survey was distributed and collected at a Continuing Medical Education course on obstetrics and gynecology.
Of 62 survey respondents, 73% are female and 87% hold MD/DO degrees. Respondents generally agree that patients want prenatal diagnostic information to help make decisions about a pregnancy and that cell-free fetal DNA testing will encourage the testing of more patients for more conditions. However, there is an overall lack of knowledge or conviction about using this technology. Genetic counseling and professional society approval are deemed important to implementation whereas the possibility of direct-to-consumer testing and government regulation produce mixed responses. Respondents indicate that they are more likely to offer cell-free fetal DNA testing for chromosomal abnormalities and single-gene disorders, but are cautious with respect to determination of sex and behavioral or late-onset conditions.
Preliminary assessment indicates uncertainty among obstetric providers about the details of implementing cell-free fetal DNA testing and suggests expanded research on perspectives of this stakeholder group.
PMCID: PMC3200428  PMID: 21793012
Psychosocial; legal, and ethical implications; cell-free fetal DNA; cell-free fetal RNA; non-invasive prenatal diagnosis; healthcare provider perspectives; clinical translation
Prenatal Diagnosis  2011;31(11):1046-1053.
To identify the frequency of pregnancy and neonatal complications in pregnancies carrying fetuses affected with trichothiodystrophy (TTD).
We identified pregnancy and neonatal complications and serum screening results from mothers of TTD patients in a DNA repair diseases study from 2001 to 2011.
Pregnancy reports of 27 TTD patients and their 23 mothers were evaluated and81% of the pregnancies had complications: 56% had preterm delivery, 30% had preeclampsia, 19% had placental abnormalities, 11% had HELLP syndrome, 4% had an emergency c-section for fetal distress; while44% had two or more complications. Only19% of the pregnancies delivered at term without complications. Eight of the 10 pregnancies tested had abnormal multiple marker results including elevated levels of human chorionic gonadotropin. Eighty-five percent of the neonates had complications: 70 % were low birth weight (<2500g), 35% had birth weight <10 centile for gestational age, 70% had NICU admission, 67% had a collodion membrane, and 31% of the 16 males had cryptorchidism. Cataracts were present in 54% of the TTD patients examined.
TTD is a multisystem disease that predisposes mothers of affected patients to substantial risks for pregnancy complications and TTD neonates have a high incidence of multiple abnormalities.
PMCID: PMC3266696  PMID: 21800331
Trichothiodystrophy; Pregnancy; Maternal Serum Screening; hCG; Preeclampsia; HELLP syndrome

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