Assisted reproductive technology (ART) cumulative live birth rates following preimplantation genetic diagnosis for aneuploidy (PGD-A) or morphological assessment of embryos: A cohort analysis.

BACKGROUND: Preimplantation genetic diagnosis for aneuploidy (PGD-A) for all 24 chromosomes improves implantation and clinical pregnancy rates per single assisted reproductive technology (ART) cycle. However, there is limited data on the live-birth rate of PGD-A over repeated cycles. AIM: To assess the cumulative live-birth rates (CLBR) of PGD-A compared with morphological assessment of embryos of up to three 'complete ART cycles' (fresh plus frozen/thaw cycles) in women aged 37 years or older. MATERIALS AND METHODS: A retrospective cohort study of ART treatments undertaken by ART-naïve women at a large Australian fertility clinic between 2011 and 2014. Cohorts were assigned based on the embryo selection method used in their first fresh cycle [PGD-A, n = 110 women (PGD-A group); morphological assessment of embryos, n = 1983 women (control group)]. CLBR, time to clinical pregnancy and cycles needed to achieve a live birth were measured over multiple cycles. RESULTS: Compared to the control group, the PGD-A group achieved a higher per cycle live-birth rate (14.47% vs 9.12%, P < 0.01), took a shorter mean time to reach a clinical pregnancy leading to a live-birth (104.8 days vs 140.6 days, P < 0.05) and required fewer cycles to achieve a live-birth (6.91 cycles vs 10.96 cycles, P < 0.01). However, after three 'complete ART cycles', the CLBR was comparable for the two groups (30.90% vs 26.77%, P = 0.34). CONCLUSION: This is the first study to assess the effectiveness of PGD-A over multiple ART cycles. These real-world findings suggest that PGD-A leads to better outcomes than using morphological assessment alone in women of advanced maternal age.

Current experience concerning mosaic embryos diagnosed during preimplantation genetic screening.

The concept of embryos containing multiple cell lines (mosaicism) is not new, but much attention has been paid to this concept recently owing to recent advances in molecular techniques to analyze human embryos. Mosaicism in embryos has been known and reported for some time, originally in early cleavage-stage embryos diagnosed with the use of fluorescence in situ hybridization (FISH). However, the early data have come under attack owing to the limited ability of FISH to reliably detect the actual copy number count of chromosomes as well as potential ascertainment bias of those early studies, which were all performed on already analyzed embryos found to be aneuploid. More recent molecular techniques for analyzing embryos have allowed scientists to really begin to understand mosaic embryos, and to now transfer and follow this class of embryo. Indeed, it could be said that three classes of embryos now exist after preimplantation genetic screening: euploid, aneuploid, and mosaic aneuploid. This paper attempts to bring to light the latest data on mosaic embryos and to understand how clinicians and others will deal with this issue today and in the future. Finally, an attempt is made to look to other fields of genetics to understand how this important issue can be dealt with as a group much better than any one individual group may be able to.

Transferring embryos with genetic anomalies detected in preimplantation testing: an Ethics Committee Opinion.

Patient requests for transfer of embryos with genetic anomalies linked to serious health-affecting disorders detected in preimplantation testing are rare but do exist. This Opinion sets out the possible rationales for a provider's decision to assist or decline to assist in such transfers. The Committee concludes in most clinical cases it is ethically permissible to assist or decline to assist in transferring such embryos. In circumstances in which a child is highly likely to be born with a life-threatening condition that causes severe and early debility with no possibility of reasonable function, provider transfer of such embryos is ethically problematic and highly discouraged.

Introduction: To transfer or not transfer a mosaic embryo, that is the question.

This issue's Views and Reviews section aims to offer readers a 360° view of the knowledge accumulated regarding the transfer of mosaic embryos by experts from around the world, as well as an in vitro fertilization worldwide survey on the topic.

Assessing the true incidence of mosaicism in preimplantation embryos.

Modern technologies applied to the field of preimplantation genetic diagnosis for aneuploidy screening (PGD-A) have improved the ability to identify the presence of mosaicism. Consequently, new questions can now be addressed regarding the potential impact of embryo mosaicism on diagnosis accuracy and the feasibility of considering mosaic embryos for transfer. The frequency of chromosomal mosaicism in products of conception (POCs) of early miscarriages has been reported to be low. Mosaic embryos with an aneuploid inner cell mass are typically lost during the first trimester owing to spontaneous miscarriages. Most of the mosaics in established pregnancies would derive from placental mosaicism or placental aneuploidy, and mosaic embryos with aneuploid inner cell mass should be lost mainly due to first-trimester spontaneous miscarriages. The well described clinical outcomes of live births from mosaic embryos suggest a wide spectrum of phenotypes, from healthy to severely impaired. Therefore, there is a need to balance the risks of discarding a possibly viable embryo with that of transferring an embryo that may ultimately have a lower implantation potential.

Mosaicism between trophectoderm and inner cell mass.

Defining the actual incidence and prevalence of mosaicism in human blastocysts still remains a difficult task. The small amount of evidence generated by animal and human studies does not support the existence of mechanisms involved in developmental arrest, clonal depletion, or aneuploidy rescue for abnormal cells in euploid/aneuploid embryos during preimplantation development. However, studies in humans are mainly descriptive and lack functional evidence. Understanding the biological mechanisms that beset preimplantation differentiation holds the potential to reveal the role of aneuploidies and gene dosage imbalances in cell fate decision, providing important clues on the origin and evolution of embryonic mosaicism. The evidence on human blastocysts suggests that a mosaic euploid/aneuploid configuration is detected in around 5% of embryos. This figure supports the extremely low level of mosaicism reported in natural and IVF pregnancies. Similarly, the clinical management of patterns consistent with the presence of mosaicism in a trophectoderm biopsy during preimplantation genetic diagnosis cycles (PGD-A) is still a controversial issue. Despite the facts that some contemporary comprehensive chromosomal screening platforms can detect mosaic samples in cell mixture models with variable accuracy and many reproductive genetics laboratories are now routinely including embryonic mosaicism on their genetic reports, a diagnosis of certainty for mosaicism in PGD-A cycles is conceptually impracticable. Indeed, several technical and biological sources of errors clearly exist when trying to estimate mosaicism from a single trophectoderm biopsy in PGD-A cycles and must be understood to adequately guide patients during clinical care.

Using family members as gamete donors or gestational carriers.

The use of adult intrafamilial gamete donors and gestational surrogates is generally ethically acceptable when all participants are fully informed and counseled, but consanguineous arrangements or ones that simulate incestuous unions should be prohibited. Adult child-to-parent arrangements require caution in order to avoid coercion, and parent-to-adult child arrangements are acceptable in limited situations. Programs that choose to participate in intrafamilial arrangements should be prepared to spend additional time counseling participants and ensuring that they have made free, informed decisions. This document replaces the document of the same name, last published in 2012 (Fertil Steril 2012;98:797-803).

Phelan-McDermid Syndrome.

Phelan-McDermid syndrome is a rare neurodevelopmental syndrome associated with severe intellectual disability, motor delay, and autistic traits. This article reviews a case of a complicated presentation of Phelan-McDermid syndrome and addresses etiology, diagnosis, and management.

Diagnosis and clinical management of duplications and deletions.

Chromosome deletions and duplications-copy number variations (CNVs)-are a major contribution to the genome variability and can be either pathogenic or not. A particular class, the microdeletions and microduplications, which alter <5 Mb, have been extensively associated with developmental delay and intellectual disability. Although their prevalence in pregnancies and newborn is relatively low, their estimates in preimplantation embryos are poorly defined. The introduction of novel technologies for preimplantation genetic diagnosis of aneuploidies (PGD-A) caused new possibilities and challenges associated with diagnosis of subchromosomal CNVs. Both technical aspects of performing genomewide microarray or next generation sequencing analysis on single cells and interpretation issues are subject of debate. The latter include the reliability of detection of CNVs from embryonic biopsies, their clinical classification based on reproductive outcomes, as well as how before and after test counseling should be organized. It is also important to consider that the current resolution of these technologies from single cells is usually >10 Mb, thus ruling out the possibility to diagnose the most important recurrent microdeletion and microduplication syndromes. Furthermore, at present we face with a lack of well-designed studies addressing the actual resolution and accuracy of CNVs detection in PGD-A and no reference databases is available to evaluate their pathogenicity. Accordingly, it seems reasonable at the moment to avoid the reporting of subchromosomal CNVs in PGD-A. However, although these issues require proper handling, they should not lead us away from providing an improved preimplantation genetic diagnosis.

Diagnosis and clinical management of embryonic mosaicism.

Embryonic mosaicism occurs when two or more cell populations with different genotypes are present within the same embryo. New diagnostic techniques for preimplantation genetic screening (PGS), such as next-generation sequencing, have led to increased reporting of mosaicism. The interpretation of mosaicism is complicated because the transfer of some mosaic embryos has resulted in live births. Mosaic embryos may represent a third category between normal (euploidy) and abnormal (aneuploidy). This category of mosaic embryos may be characterized by decreased implantation and pregnancy potential as well as increased risk of genetic abnormalities and adverse pregnancy outcomes. Euploid embryos should be preferentially transferred over mosaic embryos. Genetic counseling is necessary before the transfer of a mosaic embryo is considered. Certain types of mosaic embryos should be preferentially transferred over others. Transfer of embryos with mosaic trisomies 2, 7, 13, 14, 15, 16, 18, and 21 may pose the most risk of having a child affected with a trisomy syndrome; however, the transfer of embryos with mosaic monosomies or other mosaic trisomies are not devoid of risk. Patients must be counseled about the risk of undetected monosomies or trisomies within a biopsy specimen as well as the risk of intrauterine fetal demise or uniparental disomy with the transfer of mosaic embryos. Until more data are available, patients should be encouraged to undergo another cycle to obtain euploid embryos, when possible, rather than transferring a mosaic embryo.

The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review.

STUDY QUESTION: Is preimplantation genetic diagnosis for aneuploidy (PGD-A) with analysis of all chromosomes during assisted reproductive technology (ART) clinically and cost effective? SUMMARY ANSWER: The majority of published studies comparing a strategy of PGD-A with morphologically assessed embryos have reported a higher implantation rate per embryo using PGD-A, but insufficient data has been presented to evaluate the clinical and cost-effectiveness of PGD-A in the clinical setting. WHAT IS KNOWN ALREADY: Aneuploidy is a leading cause of implantation failure, miscarriage and congenital abnormalities in humans, and a significant cause of ART failure. Preclinical evidence of PGD-A indicates that the selection and transfer of euploid embryos during ART should improve clinical outcomes. STUDY DESIGN, SIZE AND DURATION: A systematic review of the literature was performed for full text English language articles using MEDLINE, EMBASE, SCOPUS, Cochrane Library databases, NHS Economic Evaluation Database and EconLit. The Downs and Black scoring checklist was used to assess the quality of studies. Clinical effectiveness was measured in terms of pregnancy, live birth and miscarriage rates. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Nineteen articles meeting the inclusion criteria, comprising three RCTs in young and good prognosis patients and 16 observation studies were identified. Five of the observational studies included a control group of patients where embryos were selected based on morphological criteria (matched cohort studies). MAIN RESULTS AND ROLE OF CHANCE: Of the five studies that included a control group and reported implantation rates, four studies (including two RCTs) demonstrated improved implantation rates in the PGD-A group. Of the eight studies that included a control group, six studies (including two RCTs) reported significantly higher pregnancy rates in the PGD-A group, and in the remaining two studies, equivalent pregnancies rates were reported despite fewer embryos being transferred in the PGD-A group. The three RCTs demonstrated benefit in young and good prognosis patients in terms of clinical pregnancy rates and the use of single embryo transfer. However, studies relating to patients of advanced maternal age, recurrent miscarriage and implantation failure were restricted to matched cohort studies, limiting the ability to draw meaningful conclusions. LIMITATIONS, REASONS FOR CAUTION: Relevant studies may have been missed and findings from RCTs currently being undertaken could not be included. WIDER IMPLICATIONS OF THE FINDINGS: Given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood.

The ethics of contacting family members of a subject in a genetic research study to return results for an autosomal dominant syndrome.

This case explores the ethical landscape around recontacting a subject's relatives to return genetic research results when the informed consent form signed by the original cohort of subjects is silent on whether investigators may share new information with the research subject's family. As a result of rapid advances in genetic technology, methods to identify genetic markers can mature during the life course of a study. In this case, the investigators identified the genetic mutation responsible for the disorder after a number of their original subjects had died. The researchers now have the ability to inform relatives of the subject about their risk of developing the same disease. Mark Rothstein, JD, from the University of Louisville School of Medicine, provides an overview of the medical/scientific, legal, and ethical issues underlying this case. Lauren Milner, PhD, and colleagues at Stanford University explore how the relationship between researcher and subject affect this debate. Seema Shah, JD, and colleagues at the National Institutes of Health and University of California, Los Angeles (UCLA) discuss whether and how requirements of the duty to warn are applicable in this case.

Anticlastogenic activity of flavonoid rich extract of Cassia auriculata Linn. on experimental animal [corrected].

OBJECTIVE: To determine antimutagenic activity of Cassia auriculata Linn. on chromosomal damage induced by cyclophosphamide (CP). MATERIAL AND METHODS: In the present investigation, four groups of six Swiss albino mice in each group were used. Excepting for the first group all the remaining groups were treated with CP (50 mg/kg). Mice of third and fourth group were treated with ethyl acetate extract of C. auriculata Linn. at 100 mg/kg and 200 mg/kg with CP. Metaphase of bone marrow cells of all animals were analyzed for qualitative and quantitative chromosomal aberrations. Break, fragment, deletion, Polyploidy, pulverized, ring and total aberration were observed. RESULTS: Flavonoids rich extracts of root of C. auriculata Linn. provided significant protection (P < 0.05) against CP induced chromosomal aberration. Total chromosomal aberration was found to be 12.16 and 7.33% in 100 and 200 mg/kg of extract treated animals respectively. CONCLUSION: From the present study it can was observed that ethyl acetate extract of C. auriculata Linn possess significant anti-mutagenic potential against CP induced chromosomal aberration.

Discontinuous gradient centrifugation (DGC) decreases the proportion of chromosomally unbalanced spermatozoa in chromosomal rearrangement carriers.

STUDY QUESTION: Can the proportion of unbalanced spermatozoa in chromosomal rearrangement carriers be decreased through the use of discontinuous gradient centrifugation (DGC)? SUMMARY ANSWER: DGC significantly decreases the proportion of genetically unbalanced spermatozoa in chromosomal rearrangement carriers. WHAT IS KNOWN ALREADY: Chromosomal rearrangement carriers present with a certain proportion of unbalanced gametes, which can lead to miscarriages or malformations in the offspring. There is presently no known way to select the balanced spermatozoa and use them for IVF. STUDY DESIGN, SIZE, DURATION: The proportion of unbalanced spermatozoa after DGC was compared with that before DGC in 21 patients with a chromosomal rearrangement. At least 500 spermatozoa were analysed per observation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-one male patients with a chromosomal rearrangement were included in this prospective study. They initially consulted for infertility, recurrent miscarriages or a history of abnormal pregnancy. The samples were split into two, with one part undergoing DGC and the other being immediately fixed. Fluorescence in situ hybridization was performed to establish the chromosome segregation pattern of each spermatozoon. MAIN RESULTS AND THE ROLE OF CHANCE: DGC significantly decreased the proportion of unbalanced spermatozoa in all but 1 of the 21 chromosomal rearrangement carriers (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Although DGC reduces the proportion of unbalanced spermatozoa in ejaculates from patients with chromosome rearrangements this elimination is only partial and some abnormal spermatozoa remain. Means to exclude these spermatozoa to ensure that only balanced ones are used in IVF remain to be discovered. The motility and morphology of the sperm before and after DGC were not measured. WIDER IMPLICATIONS OF THE FINDINGS: Used in IVF or intrauterine insemination, DGC could decrease the chance that a man carrying a chromosomal rearrangement will father an abnormal fetus.

Economic analysis of chromosome testing in couples with recurrent miscarriage to prevent handicapped offspring.

STUDY QUESTION: Which strategy is least expensive to prevent the birth of a handicapped child in couples with recurrent miscarriage (RM); parental chromosome analysis followed by amniocentesis in case of carrier status of one of the parents, or amniocentesis in all ongoing pregnancies without the knowledge of parental carrier status? SUMMARY ANSWER: For virtually all couples with RM amniocentesis in all ongoing pregnancies without the knowledge of parental carrier status is less expensive in preventing the birth of a handicapped child than parental chromosome analysis followed by amniocentesis in case of carrier status of one of the parents. WHAT IS KNOWN ALREADY: One of the causes of RM is a balanced chromosome abnormality in one of the partners. If one of the partners is carrier of a balanced structural chromosomal abnormality, the risk of offspring with an unbalanced structural chromosome abnormality is increased. Like all couples, couples with RM also have an age-dependent risk for fetal aneuploidy, of which trisomy 21 is most common. STUDY DESIGN, SIZE, DURATION: Model-based economic analysis to compare costs and effects of two strategies in couples with RM to prevent the birth of a handicapped child in case of ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Comparison of two strategies in women with RM: strategy (I) parental chromosome analysis followed by amniocentesis in pregnancy in case of carrier status of one of the parents and strategy (II) amniocentesis in all ongoing pregnancies without the knowledge of carrier status. No testing was the reference strategy. Data on probabilities and costs were derived from the literature. Incremental costs and effects were calculated [incremental cost-effectiveness ratio (ICER)]. Effectiveness was expressed as the number of prevented births of handicapped child equivalents compared with no testing. In these calculations, the birth of a handicapped child was valued 10 times worse than the loss of a viable pregnancy due to amniocentesis. MAIN RESULTS AND THE ROLE OF CHANCE: Depending on the risk for carrier status, the ICER for Strategy I (parental chromosome analysis followed by amniocentesis in case of carrier status of one of the parents) varied between € 226,000 and € 6,556,000 per prevented handicapped child equivalent. For Strategy II (amniocentesis in all ongoing pregnancies without the knowledge of carrier status), the ICER varied between € 2000 and € 233 000 per prevented handicapped child equivalent. Strategy I was less expensive than Strategy II only for a small subgroup of couples with maternal age <23 years, three or more previous miscarriages and a family history of RM. LIMITATIONS, REASONS FOR CAUTION: Our analysis is not a plea for amniocentesis in all women with RM. Individual risk assessment with serum markers and nuchal translucency is probably more effective at lower cost. WIDER IMPLICATIONS OF THE FINDINGS: This analysis can be used by clinicians to explain the chances of adverse pregnancy outcome in couples with RM, as well as by policy makers in health-care economics. Future guidelines on RM might be more restrictive from the perspective of the limited health-care resources that we have available.

Dietary docosahexaenoic acid supplementation prevents age-related functional losses and A2E accumulation in the retina.

PURPOSE: With age, retina function progressively declines and A2E, a constituent of the toxin lipofuscin, accumulates in retinal pigment epithelial (RPE) cells. Both events are typically exacerbated in age-related retina diseases. We studied the effect of dietary docosahexaenoic acid (DHA, C22:6n-3) supplementation on these events, using a transgenic mouse model (mutant human ELOVL4; E4) displaying extensive age-related retina dysfunction and massive A2E accumulation. METHODS: Retina function was assessed with the electroretinogram (ERG) and A2E levels were measured in E4 and wildtype (WT) mice. Dietary DHA was manipulated from 1 to 3, 1 to 6, 6 to 12, and 12 to 18 months: 1% DHA over total fatty acids (E4+, WT+) or similar diet without DHA (E4-, WT-). RESULTS: Increased omega-3/6 ratios (DHA/arachidonic acid) in E4+ and WT+ retinas were confirmed for the 1- to 3-month and 1- to 6-month trials. Although 1- to 3-month intervention had no effects, when prolonged to 1 to 6 months, RPE function (ERG c-wave) was preserved in E4+ and WT+. Intervention from 6 to 12 months led to maintained outer and inner retina function (ERG a- and b-wave, respectively) in E4+. At 12 to 18 months, a similar beneficial effect on retina function occurred in WT+; A2E levels were reduced in E4+ and WT+. CONCLUSIONS: DHA supplementation was associated with: preserved retina function at mid-degenerative stages in E4 mice; prevention of age-related functional losses in WT mice; and reduced A2E levels in E4 and WT mice at the oldest age examined. These findings imply that dietary DHA could have broad preventative therapeutic applications (acting on pathologic and normal age-related ocular processes).

Effect of Buchanania lanzan Spreng. bark extract on cyclophosphamide induced genotoxicity and oxidative stress in mice.

OBJECTIVE: To elucidate the effect of ethanolic extract of Buchanania lanzan Spreng. (B. lanan) bark against cyclophosphamide induced genotoxicity and oxidative stress in mice. METHODS: The prevalence of micronuclei in bone marrow, the extent of lipid peroxidation, reduced glutathione and the status of the antioxidant enzymes, superoxide dismutase and catalase in liver of mice were used as intermediate biomarkers for chemoprotection. Lipid peroxidation and associated compromised antioxidant defenses in cyclophosphamide treated mice were observed in the liver. RESULTS: Pre-treatment with B. lanzan 250, 500 and 1,000 mg/kg, p.o., daily for 7 days significantly reduced the chromosomal damage and lipid peroxidation with concomitant changes in antioxidants and detoxification systems. CONCLUSIONS: These results point out the presence of chemopreventive phytoconstituents in the crude extract offering protection against cyclophosphamide induced genotoxicity and oxidative stress in mice.

[Karyotype analysis of qualified sperm donors on preliminary screening].

OBJECTIVE: To explore the significance of karyotype analysis in screening sperm donors. METHODS: From January 1, 2004 to December 31, 2008, a total of 2537 potential sperm donors passed our preliminary screening, and all were routinely karyo-typed via peripheral blood. Follow-ups were conducted on the pregnancy outcome and congenital malformation after artificial insemination with the sperm from the qualified donors. RESULTS: Among the 2537 qualified sperm donors, 2362 were of the normal karyotype 46, XY and 135 showed polymorphism. Abnormal karyotype was found in 6 cases, and controversial abnormal karyotype in 34. CONCLUSION: Karyotype analysis can reduce the risk of chromosomal disease in neonates from artificial insemination, and genetic counseling for abnormal karyotype sperm donors may help them solve their future reproductive problems.

Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS).

BACKGROUND: Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances in women with diminished ovarian reserve (DOR), and to reduce miscarriage rates by 50-80%. Such an effect is mathematically inconceivable without beneficial effects on embryo ploidy. This study, therefore, assesses effects of DHEA on embryo aneuploidy. METHODS: In a 1:2, matched case control study 22 consecutive women with DOR, supplemented with DHEA, underwent preimplantation genetic screening (PGS) of embryos during in vitro fertilization (IVF) cycles. Each was matched by patient age and time period of IVF with two control IVF cycles without DHEA supplementation (n = 44). PGS was performed for chromosomes X, Y, 13, 16, 18, 21 and 22, and involved determination of numbers and percentages of aneuploid embryos. RESULTS: DHEA supplementation to a significant degree reduced number (P = 0.029) and percentages (P < 0.001) of aneuploid embryos, adjusted for relevant covariates. Short term supplementation (4-12 weeks) resulted in greatest reduction in aneuploidy (21.6%, 95% CI -2.871-46.031). DISCUSSION: Beneficial DHEA effects on DOR patients, at least partially, are the likely consequence of lower embryo aneuploidy. DHEA supplementation also deserves investigation in older fertile women, attempting to conceive, where a similar effect, potentially, could positively affect public health.

Low uptake of prenatal diagnosis after established carrier status of a balanced structural chromosome abnormality in couples with recurrent miscarriage.

OBJECTIVE: To evaluate to what extent couples carrying a balanced structural chromosome abnormality follow up the advice to opt for invasive prenatal diagnosis (PND) in subsequent pregnancies. DESIGN: Index-control study. SETTING: Six centers for Clinical Genetics in The Netherlands. PATIENT(S): Couples referred for chromosome analysis after recurrent miscarriage between 1992 and 2001 and with at least one pregnancy after disclosure; 239 carrier couples and 389 noncarrier couples. INTERVENTION(S): Questionnaire, medical record checking. MAIN OUTCOME MEASURE(S): Uptake of invasive PND. RESULT(S): Only 53 of 239 (22%) carrier couples underwent a PND procedure (CVS or amniocentesis) in all subsequent pregnancies. A relatively high number, 105 (44%) carrier couples, refrained from PND in all subsequent pregnancies. More carrier couples with maternal age >or=36 years (20/33 = 61%) refrained from PND, compared with carrier couples with maternal age <36 years (85/206 = 41%). In women >or=36 years, an equal proportion of carrier and noncarrier couples refrained from PND (61% vs. 54%). CONCLUSION(S): The advice to opt for invasive PND in carrier couples is poorly followed, especially in carrier couples with maternal age >or=36 years. The motivations of carrier couples to opt for or refrain from invasive PND procedures should be the topic for further research to optimize clinical care and informative decision making.