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Study Question: Can a core outcome set to standardize outcome selection, collection, and reporting across future infertility research be developed?, Summary Answer: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCT) and systematic reviews evaluating potential treatments for infertility., What Is Known Already: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions, and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret., Study Design, Size, Duration: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries)., Participants/materials, Setting, Methods: Healthcare professionals, researchers, and people with fertility problems were brought together in an open and transparent process using formal consensus science methods., Main Results and the Role of Chance: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth, and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable., Limitations, Reasons for Caution: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition, and an arbitrary consensus threshold., Wider Implications of the Findings: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection, and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Ferility and Sterility, and Human Reproduction, have committed to implementing this core outcome set., Study Funding/competing Interest(s): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund, and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. Hans Evers reports being the Editor Emeritus of Human Reproduction. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Annika Strandell reports consultancy fees from Guerbet. Ernest Ng reports research sponsorship from Merck. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form., Trial Registration Number: Core Outcome Measures in Effectiveness Trials Initiative: 1023., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Disorders of genetic etiology exist in 2%-3% of live-born infants. Identifying couples with increased susceptibility for offspring with anomalies or genetic disorders is increasingly effective as a result of molecular advances. Preimplantation genetic testing (PGT) with the use of trophectoderm biopsy, 24-chromosome testing, and molecular testing have allowed wider applicability for avoiding a clinical pregnancy termination. Cell-free DNA in maternal blood is another targeted option, although invasive prenatal genetic diagnosis provides the greatest amount of genetic information. DNA-based methods to detect subtle chromosomal abnormalities are much more sensitive than traditional karyotypes and do not require cultured cells. Aneuploidy and structural chromosomal abnormalities can be readily detected with the use of small amounts of DNA, if necessary amplified, as in PGT. Novel approaches exist for detecting perturbations in single-gene disorders. Not only has the molecular basis for many monogenic disorders been elucidated, but modest costs for DNA sequencing has made testing feasible. As the number of testable genetic disorders has increased, principles underlying screening have advanced. Genetic screening for disorders of high incidence in certain ethnic groups was initiated decades ago; however, limitations exist, and reduction in live-born incidence is not infrequently small. Expanded carrier screening is now offered in panethnic fashion, extending surveillance to couples of mixed ethnicities and involving many more genetic conditions. Targeted gene panels (e.g., adult-onset cancer genes) further increase the number of genetic disorders amenable to screening, often leading to PGT., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Couples at risk for autosomal recessive congenital adrenal hyperplasia often request anticipatory guidance and genetic counseling. Initially, hormones in amniotic fluid were measured to distinguish affected female fetuses from unaffected fetuses. With the molecular era, more-targeted approaches became possible. Prenatal genetic diagnosis via amniocentesis or chorionic villus sampling was used to determine the need for continuing fetal therapy (dexamethasone), allowing cessation if the fetus was unaffected. Newer methods now allow diagnosis earlier in gestation, further shortening the treatment time for unaffected female fetuses who will not develop genital ambiguity. Preimplantation genetic testing permits transfer only of an unaffected female or male fetus. Analysis of maternal cell-free DNA based on quantitative differences in the amount of allele parental DNA permits affected pregnancies to be differentiated from unaffected pregnancies., (Copyright © 2018. Published by Elsevier Inc.)

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Question: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems?, Summary Answer: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders., What Is Known Already: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues., Study Design, Size, Duration: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions., Participants/materials, Setting, Methods: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations., Main Results and the Role of Chance: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion., Limitations, Reasons for Caution: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary., Wider Implications of the Findings: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide., Study Funding/competing Interests: None., Trial Registration Number: N/A., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the association between human empty spiracles homeobox 2 gene (EMX2) and incomplete müllerian fusion (IMF)., Design: Case-control study., Setting: University-based hospital., Patient(s): Cohort of 517 clinically well-characterized IMF cases and 563 control women., Intervention(s): None., Main Outcome Measure(s): In cases and control women, direct sequencing of EMX2 exons and further functional studies; for functional studies, wild-type and mutant EMX2 expression plasmids constructed; human embryonic kidney cells (HEK293FT) transfected with empty vector, wild-type EMX2, mutant EMX2, and 1:1 combination (wild-type/mutant plasmids) with additional functional studies performed to clarify the deleterious effect of the novel mutation detected., Result(s): A novel nonsense mutation p.E142X was detected in one woman with a didelphic uterus (1 of 517, 0.19%). The results of Western blot analysis confirmed that the mutation caused a truncated protein as predicted, and functional studies proved that it resulted in a dominant negative effect., Conclusion(s): The novel nonsense mutation we detected-EMX2, p.E142X- resulted in a dominant negative effect. The functional data were exemplified in HEK293FT cells. This reinforced the likelihood that EMX2 contributed to the pathophysiology of IMF. Although it is uncommon (0.19%), EMX2 is the first gene identified that if perturbed may cause isolated IMF., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether gene variants of SOHLH1 exist in Chinese and Serbian patients with primary ovarian insufficiency (POI)., Design: Case-control genetic study., Setting: University hospitals., Patient(s): A total of 364 Han Chinese and 197 Serbian women with nonsyndromic POI and ethnically matched controls., Intervention(s): None., Main Outcome Measure(s): SOHLH1 gene sequencing., Result(s): We found 10 novel heterozygous variants in our cohorts of 561 women with POI but none in the 600 ethnically matched controls. Statistical and bioinformatic analyses indicated that three of the eight variants in Chinese POI cases are potentially disease causing. They comprise two missense variants (p.Ser317Phe and p.Glu376Lys) that might each change activity of the SOHLH1 protein as a transcription factor and one variant (c.*118C>T) located in the 3' untranslated region of the SOHLH1 gene, which might generate a new binding site for the microRNA hsa-miR-888-5p. Of the two variants in the Serbian POI cases, both were synonymous, and no missense variant was identified. The allele frequencies of some known single-nucleotide polymorphisms were statistically significantly different between patients and controls in both the Chinese and Serbian groups., Conclusion(s): Our results suggest that SOHLH1 may be regarded as a new candidate gene for POI., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether variants in the SOHLH2 gene contribute to human premature ovarian failure (POF) in different ethnicities., Design: Case-control genetic study., Setting: University hospitals., Patient(s): Chinese (364 cases) and Serbian (197 cases) women with nonsyndromic POF and ethnically matched controls., Intervention(s): None., Main Outcome Measure(s): Variation analysis of the SOHLH2 gene., Result(s): Eleven novel heterozygous variants were identified in cohorts of POF but were absent in matched controls. These included the nonsynonymous variants p.Glu79Lys (n = 2 cases), p.Glu105Gly, and p.Thr321Pro, which were found among four Chinese POF cases, and p.Leu120Phe (n = 3 cases) and p.Leu204Phe, which were found among four Serbian women. Protein alignments reveal that p.Glu79Lys and p.Glu105Gly involve amino acids highly conserved among mammals, both of which are predicted to be deleterious. The c.-210G>T found in the Chinese POF cohort lies in the core promoter region, which is enriched with transcription factor binding sites and CpG islands. In the Serbian cohort, the variant most likely to have a deleterious effect is c.530+6T>G, which is predicted to affect RNA splicing and result in nonsense mediated decay of transcripts. The other variants are less likely to be deleterious. Disturbing the expression, transactivation or homo-/ heterodimerization of the SOHLH2 protein could result in ovarian failure. Overall, four of the 11 novel variants seem plausible explanations for POF; the other seven variants are less likely but cannot be categorically excluded., Conclusion(s): Our identification of novel variants in the SOHLH2 gene, in women with POF of both Chinese and Serbian origin, strongly suggests an important role for SOHLH2 in human POF etiology., (Copyright © 2014 American Society for Reproductive Medicine. All rights reserved.)

Biomarkers can be employed for screening for fetal genetic disorders, identifying individuals at sufficiently high risk for a confirmatory invasive procedure. In this article we discuss prenatal genetic aneuploidy screening. Maternal serum analytes and ultrasound have long been routinely offered, providing detection rates of 80% to 93% for trisomy 21; however, an invasive procedure (false-positive) must be performed in 5% of pregnancies screened. Recovering fetal cells from maternal blood initially proved inconsistent, but new methods recovering trophoblasts offer promise for detecting disorders using a single fetal cell, analogous to preimplantation genetic diagnosis. Current emphasis is focused predominantly on cell-free fetal DNA, which accounts for 5% to 10% of total cell-free DNA in maternal blood. Analysis of maternal blood results in detection rates of over 99% for fetal trisomy 21, and also very high rates for trisomy 18 and sex chromosomal abnormalities. Such detection rates are substantively higher than with maternal serum analytes, and are accompanied by a much lower (<1%) false-positive rate., (Copyright © 2013. Published by Elsevier Inc.)

The newborn ovary homeobox gene (NOBOX) is an oocyte-specific homeobox gene that plays a critical role in early folliculogenesis, thus representing an attractive candidate gene for nonsyndromic ovarian failure. We investigated whether perturbation in the homeodomain region of NOBOX was present in Chinese women with premature ovarian failure (POF). We sequenced 200 Chinese patients with POF, and discovered only two known single nucleotide polymorphisms: in intron 6 (c.1154+11 T>C and c.1155-22 G>A); neither offers plausible explanations for POF. Failing to find causative mutation contrasts with our previous study in a caucasian sample, in which we found plausible homeobox mutation in 1 of 96 POF cases. Mutations in the homeobox domain of NOBOX are not common explanations for POF in Chinese women.

The oocyte-specific G-protein-coupled receptor 3 (GPR3) gene is essential in maintaining meiotic arrest in mouse oocytes. Disruption of GPR3 results in early depletion of oocytes and thus premature ovarian aging. To determine if mutations of the GPR3 gene were present in 82 predominantly North American caucasian women with premature ovarian failure (POF), we used denaturing high-performance liquid chromatography and DNA sequencing to detect sequence variants. None of the 82 POF samples showed perturbations of significance. We conclude that perturbations in GPR3 are not a common explanation for POF in this population.

The LHX8 (LIM homeobox 8) gene encodes a LIM homeodomain transcriptional regulator that is preferentially expressed in germ cells and critical for mammalian oogenesis. The authors investigated whether nucleotide changes were present in the LHX8 gene of Caucasian women with premature ovarian failure (POF), as compared with control women. When the authors sequenced 95 Caucasian women with POF, they discovered two novel single-nucleotide polymorphisms (SNPs) in intron 3 (c.769+10G>T) and 3' untranslated region (c.1787A>G) of the LHX8 gene. These polymorphisms also were found in controls (n = 94), at frequencies that were not statistically different from those in POF women. Mutations in the LHX8 exons are uncommon in Caucasian women with POF.

NANOS3 encodes an RNA-binding protein and has a conserved function in germ cell development. Our objective was to investigate whether mutations in NANOS3 were present in Chinese and Caucasian women with premature ovarian failure. A known synonymous single-nucleotide polymorphism (rs 2016163) in exon 1 was identified through sequencing 80 Chinese and 88 Caucasian women with premature ovarian failure. No additional single-nucleotide polymorphisms or mutations were found in exons encoding for NANOS3. Our findings suggest that mutations in NANOS3 exons are rare in both Chinese and Caucasian women with premature ovarian failure.

We screened growth differentiation factor 9 coding regions for mutations in a Chinese sample of 100 women with premature ovarian failure and discovered four novel single-nucleotide polymorphisms: c.436C>T (p.Arg146Cys), c.588A>C (silent), c.712A>G (p.Thr238Ala), and c.1283G>C (p.Ser428Thr). Nonsynonymous single-nucleotide polymorphisms c.436C>T and c.1283G>C were also detected in the control population. The c.712A>G perturbation results in a missense mutation (p.Thr238Ala) and was not present in any of 96 controls. Substitution of the hydrophobic amino acid residue alanine for hydrophilic threonine may disrupt growth differentiation factor 9 function.

Objective: To update clinicians on the reproductive implications of premutations in FMR1 (fragile X mental retardation 1). Fragile X syndrome, a cause of mental retardation and autism, is due to a full mutation (>200 CGG repeats). Initially, individuals who carried the premutation (defined as more than 55 but less than 200 CGG repeats) were not considered at risk for any clinical disorders. It is now recognized that this was incorrect, specifically with respect to female reproduction., Design and Setting: Literature review and consensus building at two multidisciplinary scientific workshops., Conclusion(s): Convincing evidence now relates the FMR1 premutation to altered ovarian function and loss of fertility. An FMR1 mRNA gain-of-function toxicity may underlie this altered ovarian function. There are major gaps in knowledge regarding the natural history of the altered ovarian function in women who carry the FMR1 premutation, making counseling about reproductive plans a challenge. Women with premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Specialists in reproductive medicine can provide a supportive environment in which to explain the implications of FMR1 premutation testing, facilitate access to testing, and make appropriate referral to genetic counselors.

Objective: To determine whether perturbations of the growth differentiating factor-9 (GDF9) gene are associated with premature ovarian failure (POF)., Design: Mutational analysis of the GDF9 gene in 61 women with POF., Setting: Academic institution., Patient(s): Sixty-one women with POF; 60 control women., Intervention(s): Peripheral blood sampling, genomic DNA extraction, mutational screening, and DNA sequencing., Main Outcome Measure(s): Genetic perturbations in GDF9 that are associated with POF., Result(s): A single missense mutation, substitution of a cytosine residue with thymidine in exon 1 of GDF9, was found in a white woman in whom POF developed at age 22. This mutation occurred in a highly conserved proprotein region and resulted in replacement of a nonpolar amino acid (proline) with a polar amino acid (serine) at position 103. Neither 60 control women nor 60 other women with POF demonstrated this genetic perturbation. Exon 2 showed only previously recognized single nucleotide polymorphisms., Conclusion(s): GDF9 mutations may be one explanation for POF, albeit uncommon.

Professional societies that are stakeholders in preimplantation genetic diagnosis have democratically elected officers and favor self-regulation. Their practice guidelines are cognizant of societal needs and allow for introduction of new technologies. These societies have demonstrated the ability for professional self-regulation by collection, validation, and promulgation of center-specific results.

Objective: To investigate quantitative aberrations involving p53 copy numbers in eutopic endometrial and endometriotic tissue from two populations., Design: Comparative analysis of normal and diseased tissue., Setting: Tissue specimens collected in Iceland and USA., Patient(s): Subjects with moderate/severe endometriosis (Iceland, n = 26; USA, n = 45). Paraffin-embedded tissue from 19 matched Icelandic cases and seven unaffected controls. American cases were fresh surgical tissue from 17 matched cases and 28 unaffected controls. DNA isolation and real-time polymerase chain reaction (PCR) with TaqMan assay were performed., Main Outcome Measure(s): The frequency of p53 loss and/or gain based on quantitative differences for copy numbers of p53 located on chromosome (17p) and GAPDH on a control locus (chromosome 12p)., Result(s): Among American cases, significant p53 gain (n = 13) or loss (n = 4) was observed in 17 of 21 cases. In Icelandic cases this was not seen to the same degree. Mean normalized p53 values were 3.46 and 1.16 copies per reaction, respectively. Significant differences were observed between normalized p53 in the control blood and affected tissue for the American and Icelandic cases compared to standard GAPDH control but not in normal Icelandic and American endometrium., Conclusion(s): The results continue to support a role for nonrandom somatic p53 locus alterations in the pathogenesis of late or severe-stage endometriosis. Differences between Icelandic and American subjects have implications for generalization of genome-wide approaches.

Objective: To determine whether preimplantation genetic diagnosis (PGD) and transfer of euploid embryos would decrease spontaneous abortion rates in recurrent miscarriage (RM) patients., Design: Controlled clinical study., Setting: In vitro fertilization centers and PGD reference laboratory., Patient(s): Recurrent-miscarriage patients with three or more prior lost pregnancies with no known etiology., Intervention(s): Biopsy of a single blastomere from each day 3 embryo, followed by fluorescence in situ hybridization analysis., Main Outcome Measure(s): The rate of spontaneous abortions in RM subjects undergoing PGD were compared with [1] their own a priori expectations and [2] a comparison group of women undergoing PGD for advanced maternal age (> or =35 years)., Result(s): Before PGD, RM patients had lost 87% (262/301) of their pregnancies, with an expected loss rate of 36.5%. After, they only lost 16.7% pregnancies. This difference was mostly due to reduction in pregnancy loss in the > or =35-years age subgroup, to 12% from an expected 44.5%., Conclusion(s): Preimplantation genetic diagnosis aneuploidy screening has a beneficial effect on pregnancy outcome in RM couples, especially those in which the woman is aged > or =35 years. Our data indicate that PGD reduces the risk of miscarriage in RM patients to baseline levels.

Tissue microarrays (TMAs) are useful tools for studying protein expression in endometriosis. Tissue microarray analyses of immunohistochemical profiles of estrogen receptor-alpha and P receptor corroborate previously published results from the use of conventional immunohistochemistry, thus validating TMA use in endometriosis.

The three respondents provide additional support for preimplantation genetic diagnosis (PGD) having the pivotal place it now has in prenatal genetic diagnosis: chromosomal abnormalities (e.g., unbalanced translocations), Mendelian disorders, and HLA typing for transfer of compatible, genetically normal, embryos. Transferring euploid embryos has decreased the clinical abortion rate and increased the implantation rate in assisted reproductive technologies (ART), but it has not necessarily improved the live-birth rate. Safer embryo biopsy, more extensive diagnostic efforts (i.e., microarray analysis), and more refined patient selection may be required before shifting from preselection of embryos based solely on morphological parameters to transfer of only aneuploidy-free embryos.

Objective: To review a 12-year experience of the world's three largest preimplantation genetic diagnosis (PGD) centers., Design: Multicenter analysis of the clinical outcome of PGD., Setting: In vitro fertilization programs at the Reproductive Genetics Institute, Chicago, Illinois; Saint Barnabas Medical Center, West Orange, New Jersey; and SISMER, Bologna, Italy., Patient(s): Poor-prognosis IVF patients, patients carrying balanced chromosomal translocations, and couples at risk for producing children with Mendelian disorders., Intervention(s): In vitro fertilization, intracytoplasmic sperm injection, polar body removal, blastomere biopsy, and ET., Main Outcome Measure(s): DNA or chromosomal analysis of biopsied polar bodies or blastomeres, implantation and clinical pregnancy rates, and live-born pregnancy outcome., Result(s): A total of 754 babies have been born as a result of 4,748 PGD attempts, which shows the expanded application and the practical relevance of PGD for single-gene disorders, chromosomal aneuploidies and translocations, late-onset diseases with genetic predisposition, and nondisease testing in couples at need for human leukocyte antigens-matched offspring for treatment of affected siblings., Conclusion(s): Preimplantation genetic diagnosis is evolving to become a clinical option for couples at risk for producing offspring with Mendelian diseases, has a positive numerical impact in standard assisted reproduction practices through aneuploidy testing, and reduces by at least fourfold the spontaneous abortion rate in couples carrying translocations.

Objective: To determine the role of antiphospholipid antibodies and anticardiolipin antibodies in first-trimester losses, addressing experimental pitfalls that preclude excluding the possibility that these antibodies reflect merely the selection bias of studying couples only after they have already experienced losses., Design: Given that retrospective studies cannot exclude the possibility that such antibodies arise as a result of the fetal death, blood samples were obtained either before pregnancy or very early in pregnancy. Sera were obtained within 21 days of conception., Setting: Multicenter university-based hospitals (National Institute of Child Health and Human Development collaborative study)., Patient(s): Subjects for the current study were 93 women who later experienced pregnancy loss (48 diabetic; 45 nondiabetic), matched 2:1 with 190 controls (93 diabetic and 97 nondiabetic) who subsequently had normal live-born offspring., Intervention(s): Sera from these 283 women were analyzed for antiphospholipid antibodies by enzyme immunoassay. In 260 of the 283 women (87 with pregnancy losses; 173 with live-born infants), sera were also available to perform assays for anticardiolipin antibodies by enzyme immunoassay., Main Outcome Measure(s): Pregnancy losses., Result(s): No association was observed between pregnancy loss and the presence of antiphospholipid antibodies or anticardiolipin antibodies. Levels of antiphospholipid antibodies were 6-19 PL/mL in 62.4% of the pregnancies that ended in losses and > or = 20 PL/mL in 5.4%; among pregnancies resulting in live-born infants, the percentages were 56.8% and 6.8%, respectively. Of the pregnancies that ended in a loss, 5.7% had anticardiolipin antibodies > or = 16 GPL/mL, compared with 5.2% of those ending in a live birth., Conclusion(s): This prospective study suggests that anticardiolipin antibodies and antiphospholipid antibodies are not associated with an increased risk for first-trimester pregnancy loss.

Objective: To obtain prospective data on the relationship between presence of antisperm antibodies in maternal sera and first trimester pregnancy losses., Design: First trimester sera obtained from diabetic and nondiabetic women recruited within 21 days of conception were analyzed using the indirect immunobead test for immunoglobulin (Ig)G, IgA, and IgM antisperm antibodies. Regional binding also was considered: sperm head, midpiece, and sperm tail. Results were correlated with pregnancy outcome., Setting: Five university centers., Patients: One hundred eleven women who experienced pregnancy loss (55 diabetic; 56 nondiabetic) were matched 2:1 with 104 diabetic and 116 nondiabetic women (controls) who subsequently had a normal liveborn infant., Intervention: None., Main Outcome Measure: Pregnancy outcome (spontaneous abortion, liveborn) correlated with presence or absence of antisperm antibodies., Results: Analyzing samples without knowledge of clinical status, no differences were observed with respect to IgG, IgA, and IgM binding when a positive test was defined as 50% of sperm showing antibody binding. Likewise, no association was found for IgG and IgM antisperm antibodies at 20% binding. The only positive finding was observed for IgA antisperm antibodies at 20% binding (Fisher's Exact test). This one positive finding merely could reflect multiple comparisons. No significant differences between groups were observed when analysis was stratified according to location of antibody binding (head, midpiece, tail tip, entire sperm). When the sample was stratified into those having and not having a prior loss, a relationship between antisperm antibodies and pregnancy loss still was not evident., Conclusion: Further work is necessary to determine whether IgA antisperm antibodies truly are associated with pregnancy loss or whether antisperm antibodies play any role in repetitive aborters. Findings in this study suggest that antisperm antibodies do not play a major role in pregnancy loss.

Objective: To assess the risk of chromosomally abnormal offspring and discuss counseling approach when both parents carry balanced translocations., Design: Theoretical segregation analysis is performed and use of empiric data is used in genetic counseling., Setting: Patients are referred to Division of Reproductive Genetics at the University of Tennessee, Memphis., Patients, Participants: The mother, heterozygous for reciprocal translocation 46,XX, rcp(7;13)(p21;q22) and father, heterozygous for Robertsonian translocation 45,XY,rob(13q;14q) were referred for genetic counseling concerning risks of chromosomally abnormal offspring., Interventions: Segregation analysis, genetic counseling, and chorionic villus sampling., Main Outcome Measure(s): A cumulative risk was derived to use for counseling purposes. Cytogenetics using GTG-banding was performed on cultured chorionic villus cells., Results: Theoretical risk of this couple having chromosomally abnormal offspring was 40.5%. On the basis of empirical data and risk factors inherent in the specific translocations, the maternal contribution at midtrimester was 3.5%; the paternal contribution was 1% to 2%. The sum of these risks was used in counseling., Conclusions: The fetus was found to be 46,XY,rcp(7;13)(p21;q22).

To elucidate further the reproductive effects of human leukocyte antigen (HLA) sharing among spouses, we have been investigating prospectively the relationship between HLA-A, -B, and -DR sharing and reproductive outcome in the Hutterites, a religious isolate that proscribes contraception. For the first time the reproductive effects of HLA-DR sharing in a fertile population is reported in this article. Median intervals from marriage to first through fifth births were longer among couples who shared more than one HLA-A, -B, or -DR antigen. Longer intervals were associated with increased spontaneous abortion rates among couples who shared HLA-DR antigens (27%), compared with couples who shared only HLA-A or -B antigens (9%) and couples who shared no antigens (12%). Median completed family sizes were 5.0, 8.5, and 8.0 among the groups, respectively. However, some couples who shared HLA-DR antigens experienced no spontaneous abortions, despite ten or more pregnancies. Therefore, although HLA-DR compatibility, per se, is not deleterious, our data suggest a potentially important role for undefined HLA-linked genes in normal pregnancy.

The genetics of Müllerian aplasia (absent fallopian tubes, absent or rudimentary uterine corpus and cervix, absent upper vagina) has never been investigated systematically. Some investigators believe the disorder is inherited in female-limited autosomal dominant fashion, males transmitting the mutant gene but, of course, not manifesting the trait. To investigate this possibility, we obtained pedigrees in 23 probands with Müllerian aplasia. None had an affected relative. The absence of affected individuals among 30 postpubertal sisters, 31 paternal aunts, and 40 maternal aunts makes it unlikely that a sex-limited autosomal dominant gene is a common cause of Müllerian aplasia in our population. Dominant genes might exist in other populations, and fresh dominant mutations cannot be excluded. However, polygenic/multifactorial inheritance is perhaps more plausible.

The frequency of neither hypermodal cells (2N = 47) nor hypomodal cells (2N = 45) differed between lymphocytes of individuals experiencing repetitive spontaneous abortions (N = 429) and controls (N = 90). The same conclusion held when data were analyzed according to chromosome involved (sex chromosome, autosome) or other variables (e.g., prior reproductive outcome). A study of this relatively large sample failed to confirm findings of smaller and sometimes uncontrolled studies. Hypermodal cells do not necessarily serve as a clue to meiotic instability and in turn probably do not identify couples at risk for recurrent aneuploidy.

Parental chromosomal rearrangements represent a well-established cause of repetitive spontaneous abortions. However, the frequent of parental translocations varies widely in reported series, suggesting differences in ascertainment. For this reason a sample of individuals (120 women, 104 men) who had experienced spontaneous abortions but neither stillborn nor anomalous liveborn infants was investigated. Only one translocation was detected (0.4% of individuals). The relatively low frequency of translocations in this series of probably a reflection of not only lack of coexisting stillborn or anomalous infants but also the referral pattern in this unit that facilitates routine analysis of all couples experiencing repetitive abortions. In addition, one women showed a pericentric inversion.

Familial aggregates of incomplete Müllerian fusion have been reported, but the role of genetic factors has not been elucidated. In the last several years, we have fortuitously encountered three families in which several members were affected with Müllerian fusion anomalies. In two families, several members had incomplete Müllerian fusion as traditionally described. In the third family, several members had the hand-foot-genital syndrome, a rare autosomal dominant disorder characterized not only by Müllerian fusion defects but also by skeletal (hand and foot) malformations. The etiologic heterogeneity of Müllerian fusion defects is considered.

During the years 1977 to 1986, cytogenetic studies were performed on 342 women and 297 men whose reproductive history included one or more first trimester spontaneous abortions. Thirty-nine women and 35 men experienced not only early fetal losses but also one or more stillborn infants, liveborn anomalous infants, or early neonatal deaths. Among the 303 women and 262 men evaluated solely because of repetitive abortions, only 1 woman and 1 man showed a translocation. Two translocations were detected among the 39 women and 35 men having not only repetitive abortions but also a stillborn infant, anomalous liveborn, or unexplained neonatal death. Only among the 25 women having abortions and other abnormal perinatal events was the frequency of translocations high (2/25 or 8%). Our data continue to indicate that balanced chromosomal translocations are relatively infrequent in individuals having repeated abortions but no other adverse perinatal outcome.