Diagnosis Of Unexplained Infertility Research Articles

Investigating the role of sperm-specific RNA to screen men with unexplained infertility

To identify the compartmentalization of candidate gene clusters within the human spermatozoon that contribute to spermatozoal fertilization capacity and embryo developmental competence. Sequencing and differential expression of sperm-specific RNAs in men with unexplained infertility. Consenting men screened for infertility donated their ejaculated semen samples during a 15-month period. Donors with proven fertility served as controls. RNA was isolated from 25x106 human spermatozoa using a commercially available spin column kit. Spermatozoal RNA concentration was subsequently assessed. Illumina stranded RNA sequencing (RNA-Seq) library preparation was used to construct paired-end libraries. Pilot sequencing was expanded to 50-60M reads at 2x76bp. RNA expression was calculated in fragments per kilobase of transcript per million mapped reads (FPKM). Differentially expressed RNA transcripts were identified and classified into gene clusters based on sperm-specific components i.e., the acrosome, nucleus, mid-piece, and flagellum. The expression of these transcripts was compared with standard semen parameters, and between the study and control groups. Thirty-one men with a mean age of 39.6±5 years had the following semen parameters: 46.3±19 x 106/mL concentration and 44.8±14% motility. The age of the female partner in the study and control groups was comparable. Differentially expressed RNA transcripts between the study and control groups were grouped into sperm-specific clusters: DPY19L2 and ATP6V1E2 (acrosomal); APLF, CYUB5R4, ERCC4, MORC1, PIWIL1, TNFRSF21, TSSK6 and H1FNT (nucleus); ADCY10, SMCP, PLK4 and AGPAT2 (mid-piece); and, AKAP4 and CATSPER1 (flagellum). There was a strong correlation between the expression of ATP6V1E2 and fertilization rates (R2 0.63; P<0.001) in men who underwent ICSI. A positive correlation between AKAP4 and motility was also noted (R2 0.40; P=0.01). The gene cluster localized to the nucleus was significantly under-expressed in the study group when compared to the control group (P<0.001). Interestingly, the expression of APLF, CYUB5R4, ERCC4, and TNFRSF21 was found to be higher in men <40 years (47.2±15 FPKM) compared to those >40 years (13±9 FPKM; P=0.02). Functional assessment of the gene cluster specific to certain compartments of the human spermatozoon may supplement standard semen analysis and serve as a vital tool in the diagnosis of unexplained infertility. This may further facilitate tailoring of assisted fertility treatments, thereby reducing the time to pregnancy.

IVF outcomes in young patients with unexplained infertility: an analysis of 273,779 cycles from the 2011-2013 society for assisted reproductive technology clinic outcome reporting system registry

To determine if young patients (age ≤ 25yo) with the diagnosis of unexplained infertility have poorer IVF outcomes than older women with the same diagnosis or than young women with an infertility diagnosis unrelated to age (male or tubal factor infertility).

Is there any relationship between unrecognized Celiac disease and unexplained infertile couples?

Celiac Disease (CD) is a chronic autoimmune disease characterized by small intestinal malabsorbtion and diarrhea, triggered by the ingestion of food products containing gluten. There are studies reporting that some nutritional deficiencies and some factors related to immunity may cause a decrease in fertility as well as some problems in sperm parameters. The prevalence of CD in unexplained infertility (UEI) couples is not as high as that mentioned in some reports. There is no accurate knowledge about the prevalence of CD in a UEI couple. A total of 68 couples with UEI who were admitted at Türk Diyanet Vakfı 29 Mayıs Hospital Center of in vitro fertilization (IVF) between January and June 2014 were included in this prospective pilot study. The diagnosis of UEI was made with basic infertility tests. A history of CD was questioned in the initial evaluation. Anti-gliadin, anti-endomysial, and tissue transglutaminase antibodies as well as total IgA were tested. Gastroscopy was performed in patients with positive serologic tests. Histopathological CD diagnosis was made according to Marsh criteria. The mean age of the study population was 33.40±4.59 years. Out of the 65 couples who were included into the study group, one of the five couples was positive for the autoantibodies (7.69%). Out of these 65 couples, none of them had autoantibody positivity at the same time in both partners. Anti-gliadin antibodies were found to be positive for two females out of five couples and in three male partners of the same group. Out of these five couples, only one male partner had all the antibodies as positive (1.5%). In the histopathological examination of patients with positive autoantibodies, only the patient in whom all autoantibodies were positive had findings compatible with Marsh IIIa gluten enteropathy. Only one couple had a diagnosis of CD (1.5%). In many studies, CD was shown to affect the reproductive system of women. CD may also cause a decrease in fertility in men by affecting sperm motility and androgen levels. Our study is based on a limited sample size. Our data should be confirmed in a larger cohort of subjects. These results suggest that investigation of both couples with a diagnosis of UEI may be more beneficial in clarifying the etiology.

Negative life events have detrimental effects on in-vitro fertlization outcome

The aim of this study was to investigate the effect of negative life events on in-vitro-fertilization (IVF) outcome. Depression and negative life events were measured using Beck Depression Inventory (BDI) and List of Recent Events in 83 women attending the IVF clinic of a tertiary research and education hospital with the diagnosis of unexplained infertility between January 2013 and August 2013. Demographic features, stimulation parameters, depression scores, and negative life events of pregnant and non-pregnant participants were compared and the relation between negative life events, depression scores, and IVF outcome was investigated. Women who did not achieve a pregnancy experienced more negative life events than women who became pregnant (77.2% vs. 23.1%) (p > 0.001). The number of patients with moderate-to-severe depression (BDI scores > 16) was higher in the non-pregnant group than pregnant group (49.1% vs. 26.9%), however the difference was not statistically significant (p = 0.057). Clinical pregnancy showed a significant moderate negative correlation with the number of negative life events (r = −0.513, p = 0.001), but the correlation between clinical pregnancy and BDI scores was not statistically significant (r = −0.209, p = 0.059). Stressful life events have a negative influence on the quality of life, which eventually affects in IVF outcome, possibly through maladaptive lifestyle behavior.

Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility

Folic acid supplements are commonly used by infertile women which leads to a positive folate status. However, the effect of folic acid supplements on pregnancy outcome in women with unexplained infertility has not been well investigated. This study evaluated folic acid supplement use and folate status in women with unexplained infertility in relation to IVF pregnancy outcome. In addition, use of folic acid supplements and folate status were compared between women with unexplained infertility and fertile, nonpregnant control women. Women with unexplained infertility used significantly more folic acid supplements and had higher median total folic acid intake from supplements compared with fertile control women (both P<0.001). Women with unexplained infertility also had significantly higher median plasma folate and lower median plasma homocysteine concentrations than fertile women (both P<0.001), but folic acid supplementation or folate status were not related to pregnancy outcome in women with unexplained infertility. In conclusion, folic acid supplementation or good folate status did not have a positive effect on pregnancy outcome following infertility treatment in women with unexplained infertility.Folate is one of the B vitamins which has been suggested to be related to infertility. Folic acid is an artificial form of folate which is commonly used in dietary supplements. Folic acid supplementation has been shown to increase folate concentrations and decrease concentrations of the amino acid homocysteine in the blood. Folic acid supplementation is commonly used by infertile women, but the effect on pregnancy outcome in women with a diagnosis of unexplained infertility has not been thoroughly investigated. In the present study, folic acid supplement use and folate status (concentrations of folate and homocysteine) in women with unexplained infertility were evaluated in relation to pregnancy outcome. In addition, the use of folic acid supplements and folate status were compared between women with unexplained infertility and fertile control women. Our results showed that women with unexplained infertility used considerably more folic acid supplements and had higher total folic acid intake from supplements compared with fertile control women. Women with unexplained infertility had better blood folate and homocysteine concentrations than fertile women, but folic acid supplementation or folate status were not related to pregnancy outcome following the infertility treatment. In conclusion, high folic acid intake or good folate status did not increase the possibility of a birth of a healthy baby after infertility treatment in women with unexplained infertility.

Definition and epidemiology of unexplained infertility.

The diagnosis of unexplained infertility can be made only after excluding common causes of infertility using standard fertility investigations,which include semen analysis, assessment of ovulation, and tubal patency test. These tests have been selected as they have definitive correlation with pregnancy. It is estimated that a standard fertility evaluation will fail to identify an abnormality in approximately 15% to 30% of infertile couples. The reported incidence of such unexplained infertility varies according to the age and selection criteria in the study population. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1950 and 2013. Since first coined more than 50 years ago, the term unexplained infertility has been a subject of debate. Although additional investigations are reported to explain or define other causes of infertility, these have high false-positive results and therefore cannot be recommended for routine clinical practice. Couples with unexplained infertility might be reassured that even after 12 months of unsuccessful attempts, 50% will conceive in the following 12 months and another 12% in the year after.

The association of trefoil factor 3 gene polymorphisms and haplotypes with unexplained female infertility: Molecular insights into TFF3 regulation in receptive phase endometrium

This study examined the genetic variation within the gene trefoil factor 3 (TFF3) in relation to unexplained female infertility in a group of women where aberrant endometrial maturation was suspected. The study consisted of 113 women with a diagnosis of unexplained infertility and 289 healthy fertile volunteers. Five single nucleotide polymorphisms rs225439, rs533093, rs225361, rs11701143, and rs77436142 within TFF3 gene were analyzed using real-time PCR. The formed haplotype pattern within the TFF3 gene in relation to infertility was also assessed. TFF3 protein localization and expression in receptive stage endometrium at the time of implantation was measured in a subset of fertile (n = 7) and infertile (n = 12) women. Allele and genotype frequencies did not differ significantly between fertile and infertile women, nor did the formed haplotypes. TFF3 protein was expressed in all cell types in receptive stage endometria in fertile and infertile women. No significant association was observed between protein expression and analyzed genotypes. A significantly higher TFF3 expression in luminal epithelial cells was detected in women with unexplained infertility (p = 0.003).

The effects of semen parameters to the outcomes of IVF/ICSI cycles in unexplained infertility and mild male factor infertility

To compare semen parameters of the patients with the diagnosis of unexplained infertility and mild male factor infertility undergoing IVF/ICSI cycles and to determine the effects of these parameters on treatment outcomes.

Endometrial spiral artery Doppler parameters in unexplained infertility patients: is endometrial perfusion an important factor in the etiopathogenesis?

Uterine perfusion, particularly the endometrial blood flow, may have an important role in endometrial receptivity. In order to assess the contribution of sub endometrial blood flow in the etiopathogenesis of unexplained infertility mid luteal- peri-implantation period spiral artery transvaginal color Doppler parameters were measured and compared with fertile controls. Forty-two consecutive patients admitted to Izmir Katip Celebi University Ataturk Training and Research Hospital, Department of Obstetric and Gynecology with the diagnosis of unexplained infertility after standard diagnostic work up constituted the study group and they were compared with a fertile control group admitted to hospital with non specific gynecological complaints or for check-up in the same period. Mid luteal transvaginal color Doppler ultrasonography was applied to each patient by the same radiologist who was blind to the diagnosis of the particular patient and, RI (resistance index) and PI (pulsatility index) values were calculated. There were no significant differences between the two groups, in respect to age, body mass index, basal hormonal and mid luteal progesterone levels (p>0.05). For the fertile control group, mid luteal-peri-implantation phase endometrial spiral artery mean RI values were calculated as 0.48±0.08 SD and mean PI values as 0.65±0.18 SD. For the study group, mean RI values were calculated as 0.54±0.07 SD, PI values were calculated as 0.80±0.16 SD. The differences for RI (p=0.009) and PI (p=0.004) were statistically significant. According to Doppler parameters, unexplained infertility patients have high impedance blood flow in spiral arteries which means that peri-implantation blood flow in these patient is lower than fertile controls. These findings suggest that endometrial perfusion may have an important contribution to etiopathogenesis of unexplained infertility.

Does Immunotherapy for Treatment of Reproductive Failure Enhance Live Births?

Before effective treatment for reproductive failure can be instituted, the cause of the failure must be determined. A search of PubMed was made to identify the published data regarding diagnosis and treatment of reproductive failure. Results were compared with the frequency of antiphospholipid antibodies (APA) in 2995 women with histories of unexplained infertility, recurrent implantation failure, recurrent pregnancy loss, and fertile women. In addition, pregnancy outcomes among 442 women experiencing reproductive failure and elevated NK cell activity after treatment with intravenous immunoglobulin (IVIg) (N = 242) or intralipids (N = 200) were compared. The prevalence of APA was the same among women with the diagnosis of unexplained infertility, recurrent implantation failure, and recurrent miscarriage. Heparin and aspirin are successful in the treatment of elevated APA among women with recurrent miscarriage but not with recurrent implantation failure. IVIg has been successful in the treatment of recurrent miscarriage and recurrent implantation failure among women with elevated APA and/or NK cell activity. When the pregnancy outcomes of women with a history of reproductive failure and elevated NK cell cytotoxicity treated with intralipid were compared with women treated with IVIg, no differences were seen. Immunotherapy for treatment of reproductive failure enhances live birth but only in those women displaying abnormal immunologic risk factors.

Long‐term cumulative pregnancy rate in women with unexplained infertility after laparoscopic surgery followed by in vitro fertilization or in vitro fertilization alone

Laparoscopy has been performed in women with unexplained infertility, but the recent trend is to commence in vitro fertilization (IVF) without prior laparoscopy. The aim of this study was to determine whether or not laparoscopic surgery is necessary for these patients. With a diagnosis of unexplained infertility, 51 women underwent laparoscopic surgery followed by IVF (laparoscopy group) and 41 women underwent IVF without prior laparoscopy (IVF group). We reviewed these two groups retrospectively and evaluated the cumulative pregnancy rate. In the laparoscopy group, 16 of the 51 women became pregnant spontaneously soon after surgery. Twenty-three patients became pregnant with IVF. In the IVF group, 32 patients became pregnant with IVF. Two of the 41 women became pregnant spontaneously while waiting to commence IVF. Laparoscopy should be offered as an option for younger patients who desire spontaneous pregnancy because there was no significant difference of the cumulative pregnancy rate between the groups.

Relationship between semen parameters and outcome of intrauterine insemination (IUI)

OBJECTIVE: The clinical relevance of the various parameters measured in routine semen analysis is not well defined. The study objective was to evaluate outcomes of IUI according to sperm concentration, motility, post-wash total motile sperm (TMS), progression and abnormal morphology. DESIGN: Retrospective review. MATERIALS AND METHODS: Records of IUI cycles performed during 2004-09 were reviewed. Inclusion criteria were female age <43 years, diagnosis of unexplained infertility and stimulation using a standard CC/FSH protocol. Analysis was restricted to the first attempt per couple during the review period. HCG (10,000 IU) was administered when there was at least one follicle >17 mm, followed 36 hours later by a single insemination with a 0.3 ml post-wash semen sample. Clinical pregnancy rate (gestational sac) was evaluated according to post-wash semen parameters (concentration, motility, TMS, and progression) of the sample used for insemination by logistic regression. For a subset of couples, percent abnormal morphology from an initial diagnostic semen analysis was also related to pregnancy outcomes by logistic regression. RESULTS: A total of 2410 couples met the inclusion criteria. Pregnancy outcomes were not significantly related to either progression (p=0.64) or sperm morphology abnormalities (p=0.15, n=1326). Pregnancy rates increased significantly with increasing TMS <8 million (p<0.0001). However, there was no apparent relationship between pregnancy and TMS ≥7 million (p=0.28). Among patients with ≥7 million TMS, neither concentration (p=0.59) nor motility (p=0.44) had any apparent effect on pregnancy rates.Tabled 1Total motile sperm<2 million≥2, <4 million≥4, <7 million≥7 millionCycles571042202029Pregnancy (%)09.614.117.4 Open table in a new tab CONCLUSION: Of all the parameters measured in routine semen analysis, the only parameter that was significantly related to IUI pregnancy outcomes was TMS. Outcomes were stable with TMS >7 million, but declined gradually with decreasing counts below 7 million.

Prospective randomized study for hydrotubation versus no hydrotubation before intrauterine insemination in unexplained infertility

The purpose of the study was to investigate the value of hydrotubation before intrauterine insemination (IUI). In 228 patients with the diagnosis of unexplained infertility, ovarian stimulation was performed before IUI, using 100mg of clomiphine citrate for 5 days from day 3 of the cycle and one ampoule of human menopausal gonadotrophin for 5 days from day 6 of the cycle. Folliculometry and determination of LH concentration in urine were performed daily until LH became positive, then randomization for hydrotubation before IUI versus no hydrotubation was performed. Fifteen patients were cancelled from the study due to poor response or stimulation of three or more follicles. A total of 213 patients were randomized as follows: 103 patients undergoing hydrotubation using 50 ml of saline and 110 patients with no hydrotubation. IUI was performed the following day and ongoing pregnancy occurred in 13 patients (12.6%) in the hydrotubation group and nine patients (8.2%) in the non-hydrotubation group with no significant difference (OR 1.66; 95% CI 0.62-4.63). In conclusion, hydrotubation before IUI does not improve pregnancy rate.

Inherited thrombophilia in infertile women: implication in unexplained infertility

Many studies evaluating a possible relationship between inherited thrombophilia and the etiology of unexplained infertility have been performed recently. No significant difference in the prevalence of three genetic mutations associated with the increased risk of thrombophilia (Factor V Leiden G1691A, prothrombin G20210A, and methylenetetrahydrofolate reductase [MTHFR] C677 T) was found in 100 infertile women with unexplained infertility when compared with 200 control fertile women without an infertility history.

Thrombophilic gene polymorphisms are risk factors for unexplained infertility

Earlier studies have shown inherited thrombophilia to be a risk factor for recurrent implantation failure, raising the question of whether this risk is related to the underlying cause of unexplained infertility or to the mechanisms involved in the implantation process. When nine thrombophilic gene polymorphisms were compared among 92 women with the diagnosis of unexplained infertility and 60 fertile control women, women with a history of unexplained infertility displayed a higher prevalence of MTHFR C677T polymorphisms than control women.

P-492: Massive multipronucleated fertilization after ICSI in patients with Reynaud′s Syndrome

The presence of multipronuclear oocytes after an IVF treatment is a multifactorial phenomenon involving the competence of both male and female gametes. ICSI has been reported to prevent the development of multipronuclear oocytes when polyspermia is thought to be the cause of multipronuclearity. Primary Reynaud′s Syndrome is a vasculopathy which was reported to be associated with infertility and poor obstetric outcome though its mechanism is still unexplained. There is no description about its perfomance in assisted reproductive techniques. We report here the ocurrence of massive multipronucleated fertilization after ICSI in two female patients suffering Reynaud′s Syndrome. Retrospective analysis. Both female patients had a diagnosis of unexplained infertility and Primary Reynaud′s Syndrome upheld by clinical and laboratory findings, with male partners being normal. Ovulation induction included the use of recombinant gonadotropins and GnRH agonists. Patient A (34 years old) underwent during 2005 an ICSI procedure after a failed IVF attempt in 2003 where 8 out of ten metaphase II oocytes had shown multipronucleation (3, 4, 6 and 7 pronuclei respectively). Patient B (32 years old) had ten metaphase II oocytes that were divided half to conventional IVF and the other half to ICSI in order to test his fertility performance and at the same time to bypass any potential hidden male factor responsible for the unexplained infertility. Four mature oocytes were retrieved from Patient A that showed 5, 7, 9 and 9 pronuclei respectively 17 hours post injection. Patient B had 10 metaphase II out of 16 oocytes retrieved. The above mentioned five oocytes inseminated by IVF showed 6, 5, 4, 4 and 3 pronuclei respectively. The other 5 oocytes injected by ICSI showed 6, 6, 3 and 0 pronuclei respectively. This is the first report that call the attention about a possible mechanism of infertility in Primary Reynaud′s Syndrome. Although ICSI can be an useful tool to prevent the appearance of multipronuclear eggs, it may not operate as an adequate technique when the ethiology is other than a failure in the mechanism to block polyspermia. Rawe (2000) reported that 21.5 % of the cases of abnormal fertilization after ICSI were due to defects in pronuclei formation ascribed to processes of diginy, diandry or subnucleation. Reference: Rawe, V. (2000). Cellular events during fertilization in humans. Dissertation submitted to obtain the PhD degree in Biological Sciences. School of Natural Sciences of The University of Buenos Aires.

Pregnancy and Implantation Rates of Donor Oocyte Recipients Obtaining Oocytes from Infertile Donors with Unexplained Infertility are Comparable to the Rates Obtained from Oocytes from Donors Whose Infertility Etiology is Tubal or Male Factor

Background and Significance: There are two main methods for supplying oocytes to women with decreased egg reserve: paid donors and donors who are trying to get pregnant by in vitro fertilization (IVF) who share half of the oocytes retrieved for reducing the cost of their own IVF procedure. Many recipients are fearful of selecting a shared donor with unexplained infertility fearing that the oocyte may be the problem, and thus only a small percentage of chosen donors have the diagnosis of unexplained infertility. Objective: The purpose of the study was to determine if a donor oocyte recipient who selects oocytes from an infertile woman with unexplained infertility has less of a chance of conception and delivery than if the oocytes were selected from infertile donors with known tubal or male factor infertility. Materials and Methods: A retrospective review of donor oocyte recipient cycles from over six years was conducted. If the recipient elected to freeze all embryos without a fresh transfer these cycles were eliminated. If a donor had endometriosis but normal tubes and a normal male partner this was considered as unexplained infertility. Results: There were 159 shared oocyte cycles evaluated as well as 403 paid oocyte fresh embryo transfers. The fertilization rates and clinical ongoing/delivered pregnancy rates and implantation rates are seen in the table below. Though there were only 12 transfers in the endometriosis and unexplained category, there were 8 clinical pregnancies (66.7% clinical pregnancy rate/cycle) and 7 ongoing delivered pregnancies (58.3%). For this combined group there were 12 embryos that implanted out of 41 that were transferred (29.2% implantation rate). Tabled 1EndometriosisTubalMale factorUnexplainedPaid donor# transfers590517394# eggs inseminated1031369660936457% fertilized69.968.264.180.669.3Avg. # embryos transferred4.03.33.23.03.0% implanted25.035.828.433.329.8% clinical pregnancy per transfer60.064.456.971.456.6% ongoing/delivered per transfer60.060.047.157.151.0 Open table in a new tab Conclusion: Donor oocytes obtained from women with unexplained infertility/endometriosis result in comparable pregnancy and implantation rates as paid donors and shared donors with diagnosis of tubal factor and male factor. Hopefully these data will encourage more recipients to choose from this category of shared donors and a larger sample size can be evaluated in the future. Though not the focus of the study, these data also show that oocytes from shared infertile oocyte donors provide recipients with comparable outcome as paid donors.

Investigation of the infertile couple: should diagnostic laparoscopy be performed after normal hysterosalpingography in treating infertility suspected to be of unknown origin?

Traditionally, a diagnosis of unexplained infertility is established only when all standard clinical investigations yield normal results. When tubal patency has been established by hysterosalpingography (HSG), laparoscopy has been suggested as a mandatory step to preclude the existence of peritubal adhesions and endometriosis as causes of infertility. In women without a previous history suggestive of tubal disease and who have a normal HSG, it was demonstrated that the probability of clinically relevant tubal disease or endometriosis is very low and that laparoscopy does not seem justified or cost effective. In the minority of these cases, laparoscopy might reveal minimal or mild endometriosis or peritubal adhesions. In these cases, either surgery or medical treatment has not been proven to improve fecundity. With the current success rates of assisted reproductive technologies (ART) and the relatively low contribution of diagnostic laparoscopy to the decision-making process of treating patients with a normal HSG, we suggest that laparoscopy should be omitted in couples suspected of having unexplained infertility. These patients should be treated by 3-6 cycles of combined gonadotrophins and intrauterine insemination, and if unsuccessful switched to ART.

Obstetric outcome in patients with unexplained infertility, Comparison of treatment‐related and spontaneous pregnancies

The aim of this study was to determine the long-term prognosis of fecundity among couples with unexplained infertility and to compare pregnancy course and outcome in spontaneous versus treatment-related pregnancies. A prospective follow-up study of 70 couples with a diagnosis of unexplained infertility. All couples had participated in a study at the Helsinki University Central Hospital where the effectiveness was compared with intrauterine insemination, direct intraperitoneal insemination or timed intercourse, each combined with superovulation. The follow-up was carried out by collecting all available information on treatment-related and spontaneous pregnancies from hospital records and questionnaires mailed to these same women 6 years later. Of 70 couples, 45 (64.3%), conceived during the follow-up period. Of all 83 pregnancies, 50 (60.2%) began spontaneously and 33 (39.8%) with infertility treatment. Rate of multiple deliveries was 25% in treatment-related pregnancies, but only 2.8% in spontaneous pregnancies (p<0.05). Mean birthweight among singleton pregnancies was 3 120 grams in treatment-related, and 3387 grams in spontaneous pregnancies (p<0.05). The rate of small-for-gestational-age (<-2 s.d.) and preterm births (before 37 completed weeks) in both groups was equal. The long-term prognosis of couples with unexplained infertility was good, and many of the pregnancies began spontaneously. The birthweight of singleton neonates in treatment-related pregnancies was lower than in spontaneously conceived pregnancies, but otherwise perinatal outcome was similar.

Evaluation of the Infertile Couple-Reply

In Reply. —Dr Seaman and colleagues appeal for a more complete investigation of the male partner as a prerequisite to the diagnosis of unexplained infertility. I agree with their contention that the male partner should see a physician. The male partner's physician might be a family physician, a urologist, or an andrologist. Alternatively, as in the Clinical Crossroads article, both partners might consult an infertility specialist. Whatever the choice, the physician should have an interest in the broad range of issues that arise in the management of infertility and should be prepared to participate in a coordinated treatment plan that meets the wishes of the couple. In the discussion section of the article, the definitions for a normal semen analysis were based on the World Health Organization laboratory manual. 1 This manual cites normal values for leukocytes in semen, an analysis that should be done routinely, and it includes methods