Ruth B. Lathi

Is infertility a risk factor for female sexual dysfunction? A case-control study

OBJECTIVE To determine the impact of infertility on female sexual function. DESIGN A case-control study. SETTING Academic infertility and gynecology practices. PATIENT(S) One hundred nineteen women with infertility and 99 healthy female controls without infertility between the ages of 18 and 45 years were included in this study. INTERVENTION(S) Anonymous survey and Female Sexual Function Index. MAIN OUTCOME MEASURE(S) Female Sexual Function Index scores, frequency of sexual intercourse and masturbation, and sex-life satisfaction. RESULT(S) Twenty-five percent of our control group had Female Sexual Function Index scores that put them at risk for sexual dysfunction (<26.55), whereas 40% of our patients with infertility met this criterion. Compared with the control group, the patients with infertility had significantly lower scores in the desire and arousal domains and lower frequency of intercourse and masturbation. The patients with infertility retrospectively reported a sex-life satisfaction score that was similar to that of the controls before their diagnosis, whereas their current sex-life satisfaction scores were significantly lower than those of the controls. CONCLUSION(S) Women with a diagnosis of infertility were found to be at higher risk for sexual dysfunction on the basis of their Female Sexual Function Index scores compared with women without infertility. The interaction of sexual function and infertility is complex and deserves further study.

Etiology of recurrent pregnancy loss in women over the age of 35 years

OBJECTIVE To determine the rate of embryonic chromosomal abnormalities, thrombophilias, and uterine anomalies in women over the age of 35 years with recurrent pregnancy loss (RPL). DESIGN Retrospective cohort study. SETTING Academic reproductive endocrinology and infertility clinic. PATIENT(S) Women>or=35 years old with >or=3 first trimester miscarriages. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Age, number of prior losses, cytogenetic testing of the products of conception (POC), uterine cavity evaluation, parental karyotype, TSH, and antiphospholipd antibody (APA) and thrombophilia testing. Aneuploidy in the POC in women with RPL was compared with sporadic miscarriages (<or=2 losses) in women>or=35 years. RESULT(S) Among 43 RPL patients, there were 50 miscarriages in which cytogenetic analysis was performed. In the RPL group, the incidence of chromosomal abnormalities in the POC was 78% (39 out of 50) compared with a 70% incidence (98 out of 140) in the sporadic losses. Thrombophilia results in the RPL patients were normal in 38 patients, four patients had APA syndrome, and one had protein C deficiency. Forty out of 43 had normal uterine cavities. Both TSH and parental karyotypes were normal in all of the patients tested. When the evaluation of RPL included karyotype of the POC, only 18% remained without explanation. However, without fetal cytogenetics, 80% of miscarriages would have been unexplained. CONCLUSION(S) In older patients with RPL, fetal chromosomal abnormalities are responsible for the majority of miscarriages. Other causes were present in only 20% of cases.

Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis.

OBJECTIVE: To report the full cohort of identifiable anomalies, regardless of known clinical significance, in a large-scale cohort of postmiscarriage products-of-conception samples analyzed using a high-resolution single-nucleotide polymorphism (SNP)–based microarray platform. High-resolution chromosomal microarray analysis allows for the identification of visible and submicroscopic cytogenomic imbalances; the specific use of SNPs permits detection of maternal cell contamination, triploidy, and uniparental disomy. METHODS: Miscarriage specimens were sent to a single laboratory for cytogenomic analysis. Chromosomal microarray analysis was performed using a SNP-based genotyping microarray platform. Results were evaluated at the cytogenetic and microscopic (greater than 10 Mb) and submicroscopic (less than 10 Mb) levels. Maternal cell contamination was assessed using information derived from fetal and maternal SNPs. RESULTS: Results were obtained on 2,389 of 2,392 specimens (99.9%) that were less than 20 weeks of gestation. Maternal cell contamination was identified in 528 (22.0%) specimens. The remaining 1,861 specimens were considered to be of true fetal origin. Of these, 1,106 (59.4%) showed classical cytogenetic abnormalities: aneuploidy accounted for 945 (85.4%), triploidy for 114 (10.3%), and structural anomalies or tetraploidy for the remaining 47 (4.2%). Of the 755 (40.6%) cases considered normal at the cytogenetic level, SNP chromosomal microarray analysis revealed a clinically significant copy number change or whole-genome uniparental disomy in 12 (1.6%) and three (0.4%) cases, respectively. CONCLUSION: Chromosomal microarray analysis of products-of-conception specimens yields a high diagnostic return. Using SNPs extends the scope of detectable genomic abnormalities and facilitates reporting “true” fetal results. This supports the use of SNP chromosomal microarray analysis for cytogenomic evaluation of miscarriage specimens when clinically indicated. LEVEL OF EVIDENCE: III

Tissue sampling technique affects accuracy of karyotype from missed abortions.

AbstractPurpose: To determine if careful specimen selection and washing of tissue from first trimester missed abortion products of conception specimens increases the sensitivity of routine cytogenetics in detecting aneuploidy. Methods: Retrospective review of cytogenetics results from tissue from dilation and curettage for missed abortion in a university fertility practice between 1998 and 2001. A technique of careful selection and washing of the specimen was implemented in July 1999. Results from before (n = 15) and after (n = 41) this change were compared. Cytogenetics reports from other physicians using the same laboratory were used for comparison (n = 59). Results: The percentage of 46XX results was significantly decreased in the test group when compared to historical and community controls: 29% vs. 73% and 56% respectively. The percentage of aneuploid results was significantly higher in the test group at 61% vs. 7% and 36% in the historical and community controls respectively. Conclusion: Thorough separation and cleaning of villi prior to sending missed abortion specimens significantly increases sensitivity of conventional cytogenetics for detecting aneuploidy by decreasing maternal contamination.

Poor Prognosis with In Vitro Fertilization in Indian Women Compared to Caucasian Women Despite Similar Embryo Quality

Background Disease prevalence and response to medical therapy may differ among patients of diverse ethnicities. Poor outcomes with in vitro fertilization (IVF) treatment have been previously shown in Indian women compared to Caucasian women, and some evidence suggests that poor embryo quality may be a cause for the discrepancy. In our center, only patients with the highest quality cleavage stage embryos are considered eligible for extending embryo culture to the blastocyst stage. We compared live birth rates (LBR) between Indian and Caucasian women after blastocyst transfer to investigate whether differences in IVF outcomes between these ethnicities would persist in patients who transferred similar quality embryos. Methodology/Principal Findings In this retrospective cohort analysis, we compared IVF outcome between 145 Caucasians and 80 Indians who had a blastocyst transfer between January 1, 2005 and June 31, 2007 in our university center. Indians were younger than Caucasians by 2.7 years (34.03 vs. 36.71, P = 0.03), were more likely to have an agonist down regulation protocol (68% vs. 43%, P<0.01), and were more likely to have polycystic ovarian syndrome (PCOS), although not significant, (24% vs. 14%, P = 0.06). Sixty eight percent of Indian patients had the highest quality embryos (4AB blastocyst or better) transferred compared to 71% of the Caucasians (P = 0.2). LBR was significantly lower in the Indians compared to the Caucasians (24% vs. 41%, P<0.01) with an odds ratio of 0.63, (95%CI 0.46–0.86). Controlling for age, stimulation protocol and PCOS showed persistently lower LBR with an adjusted odds ratio of 0.56, (95%CI 0.40–0.79) in the multivariate analysis. Conclusions/Significance Despite younger age and similar embryo quality, Indians had a significantly lower LBR than Caucasians. In this preliminary study, poor prognosis after IVF for Indian ethnicity persisted despite limiting analysis to patients with high quality embryos transferred. Further investigation into explanations for ethnic differences in reproduction is needed.

Frequency of the Male Infertility Evaluation: Data from the National Survey of Family Growth

PURPOSE An estimated 7 million American couples per year seek infertility care in the United States. A male factor contributes to 50% of cases but it is unclear what proportion of infertile couples undergoes male evaluation. MATERIALS AND METHODS We analyzed data from cycles 5 to 7 of the National Survey of Family Growth performed by the Centers for Disease Control to determine the frequency of a male infertility evaluation, and associated reproductive and demographic factors. RESULTS A total of 25,846 women and 11,067 men were surveyed. Male evaluation was not completed in 18% of couples when the male partner was asked vs 27% when female partners were asked. This corresponds to approximately 370,000 to 860,000 men in the population who were not evaluated at the time of infertility evaluation. Longer infertility duration and white race were associated with increased odds of male infertility evaluation. The male and female samples showed no change in the receipt of male examination with time. CONCLUSIONS Many men from infertile couples do not undergo male evaluation in the United States. Given the potential implications to reproductive goals and male health, further examination of this pattern is warranted.

Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation

OBJECTIVE To evaluate the pregnancy rate, ovarian responsiveness, and endometrial thickness in infertility patients with a history of methotrexate exposure who subsequently underwent controlled ovarian stimulation. DESIGN Retrospective cohort study. SETTING University reproductive endocrinology and infertility program. SUBJECT(S) Forty-eight women with infertility undergoing ovarian stimulation after receiving methotrexate treatment for ectopic gestation. INTERVENTION(S) Methotrexate administration and controlled ovarian stimulation. MAIN OUTCOME MEASURE(S) Pregnancy rate, cycle day 3 FSH levels, number of oocytes retrieved, and endometrial thickness. RESULT(S) The cumulative intrauterine pregnancy rate achieved with controlled ovarian stimulation at 2 years after methotrexate exposure was 43%, with a mean time to conceive of 181 days. Thirty-five patients with similar fertility treatments pre- and post-methotrexate were identified. Within this group, when an IVF cycle occurred within 180 days of methotrexate exposure, a significant decline in oocytes retrieved was observed. Cycles performed later than 180 days after methotrexate exposure did not exhibit a decrease in oocyte production. Endometrial development was similar at all time points examined. CONCLUSION(S) These findings suggest a time-limited and reversible impact of methotrexate on oocyte yield. If confirmed by larger clinical series and/or animal data, these results may impact the management of ectopic gestation in the patient with a history of infertility or the timing of subsequent treatments.

Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss

OBJECTIVE To evaluate the prevalence of chronic endometritis (CE) in women with recurrent pregnancy loss (RPL) and compare pregnancy outcomes in women with and without CE. DESIGN Case-control observational study. SETTING Academic fertility practice. PATIENT(S) Women with two or more pregnancy losses. INTERVENTION(S) Hematoxylin and eosin (H & E) staining was performed on all endometrial biopsies and plasma cells were identified by morphology. Immunohistochemical (IHC) staining for CD138 was later applied to all tissue samples. Charts were reviewed to evaluate the outcome of the next clinical intrauterine pregnancy. MAIN OUTCOME MEASURE(S) Miscarriage rate and live birth rate. RESULT(S) A total of 107 women met inclusion criteria. The use of CD138 IHC staining resulted in a significantly higher prevalence of CE compared with the use of H & E staining and morphological assessment alone (56% [60/107] vs. 13% [14/107]). The 51 women with untreated CE were compared with the 45 women without CE by CD138 staining. Among those women with a subsequent pregnancy, the live birth rate in the next clinical intrauterine pregnancy after endometrial evaluation was 67.6% (23/34) in women with untreated CE and 87.1% (27/31) in women without CE. Age, body mass index (BMI), results of RPL evaluation, and number of prior losses were not significantly different between the two groups. CONCLUSION(S) CD138 IHC staining of endometrial biopsies in women with RPL provides increased sensitivity when screening for CE compared with H & E staining and morphological assessment alone. Untreated CE may contribute to poor pregnancy outcomes and deserves further investigation in a larger cohort.

Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss

Recurrent pregnancy loss (RPL) occurs in ∼5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage.

Basal follicle-stimulating hormone as a predictor of fetal aneuploidy.

OBJECTIVE To determine whether an elevated basal FSH concentration is an independent predictor of fetal aneuploidy, as measured in spontaneous abortions (SAB). DESIGN Retrospective study. SETTING Academic reproductive endocrinology and infertility center. PATIENT(S) All women with karyotypes of chorionic villi isolated from first trimester spontaneous miscarriages at the time of dilation and curettage from 1999 to 2006. The highest basal serum FSH level in the year preceding dilation and curettage was recorded. INTERVENTIONS(S) Monitoring of early pregnancy. MAIN OUTCOME MEASURE(S) Fetal karyotype. RESULTS(S) A total of 177 spontaneous miscarriages with karyotypes (70 euploid and 107 aneuploid) were identified, of which 53% were conceived by IVF. The aneuploid cohort consisted of trisomic (87%), teraploid (9.3%), and monosomic (3.7%) gestations. Using logistic regression analysis, basal FSH was not found to be independently predictive of an aneuploid gestation in our data set. CONCLUSION(S) Our data do not support the hypothesis that an elevated basal FSH concentration is associated with an increase in fetal aneuploidy. Our findings suggest that the association between diminished ovarian reserve and SAB may result from nonkaryotypic factors.