Paul Claman

Men at risk: occupation and male infertility

There is accumulating evidence that workplace exposure to toxic substances contributes to male infertility. Men suffering from infertility problems may do well to look at their occupations, where exposure to certain substances may be a contributory factor, if not a direct cause, of infertility. Most of the studies to date are either case reports or epidemiological studies (population-based, case-control, or cohort studies). Additional, controlled studies need to be done to ascertain the effects of occupational toxins on male infertility. Until then, men and their employers should work together to minimize exposure to these substances.

Pregnancy Outcomes After Assisted Reproductive Technology

OBJECTIVE To review the effect of assisted reproductive technology (ART) on perinatal outcomes, to provide guidelines to optimize obstetrical management and counselling of Canadian women using ART, and to identify areas specific to birth outcomes and ART requiring further research. OPTIONS Perinatal outcomes of ART pregnancies in subfertile women are compared with those of spontaneously conceived pregnancies. Perinatal outcomes are compared between different types of ART. OUTCOMES This guideline discusses the adverse outcomes that have been recorded in association with ART, including obstetrical complications, adverse perinatal outcomes, multiple gestations, structural congenital abnormalities, chromosomal abnormalities, imprinting disorders, and childhood cancer. EVIDENCE The Cochrane Library and MEDLINE were searched for English-language articles from 1990 to February 2005, relating to assisted reproduction and perinatal outcomes. Search terms included assisted reproduction, assisted reproductive technology, ovulation induction, intracytoplasmic sperm injection (ICSI), embryo transfer, and in vitro fertilization (IVF). Additional publications were identified from the bibliographies of these articles as well as the Science Citation Index. Studies assessing gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT) were excluded since they are rarely used in Canada. All study types were reviewed. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Key studies and supporting data for each recommendation are summarized with evaluative comments and referenced. VALUES The evidence collected was reviewed by the Genetics Committee and the Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Examination. BENEFITS, HARMS, AND COSTS The type and magnitude of benefits, harms, and costs expected for patients from guideline implementation. This guideline has been reviewed by the Genetics Committee and the Reproductive Endocrinology and Infertility Committee, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society. RECOMMENDATIONS 1. Spontaneous pregnancies in untreated infertile women may be at higher risk for obstetrical complications and perinatal mortality than spontaneous pregnancies in fertile women. Further research is required to clarify the contribution of infertility itself to adverse obstetrical and perinatal outcomes. (II-2A) 2. All men with severe oligozoospermia or azoospermia should be offered genetic/clinical counselling for informed consent and offered karyotyping for chromosomal abnormalities before attempting IVF-ICSI. They should be made aware of the availability of tests for Y chromosome microdeletion. Some patients may consider the option of donor insemination. (II-3B) 3. Couples exploring IVF-ICSI when the man has obstructive azoospermia should be offered genetic/clinical counselling for informed consent and offered genetic testing for alterations in genes associated with cystic fibrosis (CF) before attempting IVF-ICSI. (II-2A) 4. Pregnancies achieved by ovarian stimulation with gonadotropins and intrauterine insemination are at higher risk for perinatal complications, and close surveillance during pregnancy should be considered. It remains unclear if these increased risks are attributable to the underlying infertility, characteristics of the infertile couple, or use of assisted reproductive techniques. Multiple gestations remain a significant risk of gonadotropin treatment. (II-2A) 5. Pregnancies achieved by IVF with or without ICSI are at higher risk for obstetrical and perinatal complications than spontaneous pregnancies, and close surveillance during pregnancy should be considered. It remains unclear if these increased risks are attributable to the underlying infertility, characteristics of the infertile couple, or use of assisted reproductive techniques. (II-2A) 6. Women undergoing ART should be informed about the increased rate of obstetrical interventions such as induced labour and elective Caesarean delivery. (II-2A) 7. Couples suffering from infertility who are exploring treatment options should be made aware of the psychosocial implications of ART. Further research into the psychosocial impact of ART is needed. (II-2A) 8. Singleton pregnancies achieved by assisted reproduction are at higher risk than spontaneous pregnancies for adverse perinatal outcomes, including perinatal mortality, preterm delivery, and low birth weight, and close surveillance during pregnancy should be available as needed. (II-2A) 9. A significant risk of ART is multiple pregnancies. Infertile couples need to be informed of the increased risks of multifetal pregnancies. Although dichorionic twins are most common, the incidence of monochorionic twins is also increased. Risks of multiple pregnancies include higher rates of perinatal mortality, preterm birth, low birth weight, gestational hypertension, placental abruption, and placenta previa. Perinatal mortality in assisted conception twin pregnancies appears to be lower than in spontaneously conceived twin pregnancies. (II-2A) 10. When multifetal reduction is being considered for high-order multiple pregnancies, psychosocial counselling should be readily available. Careful surveillance for fetal growth problems should be undertaken after multifetal reduction. (II-2A) 11. To reduce the risks of multiple pregnancies associated with ART and to optimize pregnancy rates, national guidelines should be developed on the number of embryos replaced according to characteristics such as patients age and grade of embryos. (II-2A) 12. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks to childhood and long-term growth and development associated with ART. (II-2A) 13. Discussion of options for prenatal screening for congenital structural abnormalities in pregnancies achieved by ART is recommended, including appropriate use of biochemical and sonographic screening. (II-2A) 14. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks of congenital abnormalities associated with ART. (II-2A) 15. Couples considering IVF-ICSI for male-factor infertility should receive information, and if necessary formal genetic counselling, about the increased risk of de novo chromosomal abnormalities (mainly sex chromosomal anomalies) associated with their condition. Prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis should be offered to these couples if they conceive. (II-2A) 16. Further epidemiologic and basic science research is needed to help determine the etiology and extent of the increased risks of chromosomal abnormalities associated with ART. (II-2A) 17. Discussion of options for prenatal screening and testing for aneuploidy in pregnancies achieved by ART, adapted for maternal age and number of fetuses, is recommended, including appropriate use of biochemical and sonographic screening. (II-2A) 18. The precise risks of imprinting and childhood cancer from ART remain unclear but cannot be ignored. Further clinical research, including long-term follow-up, is urgently required to evaluate the prevalence of imprinting disorders and cancers associated with ART. (II-2A) 19. The clinical application of preimplantation genetic diagnosis must balance the benefits of avoiding disease transmission with the medical risks and financial burden of in vitro fertilization. Further ethical discussion and clinical research is required to evaluate appropriate indications for preimplantation genetic diagnosis. (III-B).

Guidelines for the Number of Embryos toTransfer Following In Vitro Fertilization

OBJECTIVE To review the effect of the number of embryos transferred on the outcome of in vitro fertilization (IVF), to provide guidelines on the number of embryos to transfer in IVF-embryo transfer (ET) in order to optimize healthy live births and minimize multiple pregnancies. OPTIONS Rates of live birth, clinical pregnancy, and multiple pregnancy or birth by number of embryos transferred are compared. OUTCOMES Clinical pregnancy, multiple pregnancy, and live birth rates. EVIDENCE The Cochrane Library and MEDLINE were searched for English language articles from 1990 to April 2006. Search terms included embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), ntracytoplasmic sperm injection (ICSI), multiple pregnancy, and multiple gestation. Additional references were identified through hand searches of bibliographies of identified articles. VALUES Available evidence was reviewed by the Reproductive Endocrinology and Infertility Committee and the Maternal-Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society, and was qualified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Exam. BENEFITS, HARMS, AND COSTS This guideline is intended to minimize the occurrence of multifetal gestation, particularly high-order multiples (HOM), while maintaining acceptable overall pregnancy and live birth rates following IVF-ET.

Predictors of treatment failure for ectopic pregnancy treated with single-dose methotrexate

OBJECTIVE To determine variables that predict treatment failure after methotrexate (MTX) treatment of ectopic pregnancy. DESIGN Retrospective cohort study. SETTING Canadian teaching hospital. PATIENT(S) Sixty patients diagnosed with and treated for ectopic pregnancy. INTERVENTION(S) A single dose of methotrexate (50 mg/m(2)) by i.m. injection. MAIN OUTCOME MEASURE(S) Resolution of serum beta-hCG or clinical evidence of treatment failure. RESULT(S) Treatment failure was observed following methotrexate administration in 65% of cases when initial beta-hCG was >4000 IU/L, but in only 7. 5% of patients when serum beta-hCG was <4000 IU/L (OR = 52.06, 95% CI 4.88-555.56). Patients who presented with pelvic pain without tenderness had treatment failure 56% of the time versus only 17% in those without pain (OR = 9.20, 95% CI 1.02-82.60). Treatment failure also occurred in 53% of patients presenting with vaginal bleeding versus 16% without bleeding (OR = 6.18, 95% CI 0.73-51.93). CONCLUSION(S) Methotrexate should not be used to treat ectopic pregnancy when initial beta-hCG is >4000 IU/L. Caution should also be exercised in using methotrexate for ectopic pregnancy when the patient presents with bleeding or pain even without tenderness.

The presence of serum antibody to the chlamydial heat shock protein (CHSP60) as a diagnostic test for tubal factor infertility

OBJECTIVE To study the utility of testing for heat shock protein 60 (CHSP60) antibodies in the diagnosis of tubal factor infertility. DESIGN Prospective case control. SETTING Canadian university hospital infertility clinic. PATIENT(S) Women presenting for infertility investigation. INTERVENTION(S) Sera were collected from 77 patients. MAIN OUTCOME MEASURE(S) The relationship between tubal factor infertility and the presence of antibodies to Chlamydia trachomatis and CHSP60 was assessed. RESULT(S) There were no significant differences between antibodies to C. trachomatis in women with tubal factor infertility (63%) and other causes of infertility (46%). However, more women with tubal factor infertility (44%) had anti-CHSP60 antibodies compared with other causes of infertility (8%). Antibody testing for C. trachomatis has only a 63% sensitivity and a 54% specificity for detecting tubal factor infertility. In contrast, the CHSP60 antibody test has a 44% sensitivity and a 92% specificity for detecting tubal factor infertility. There is a good positive likelihood ratio of 5.5 for CHSP60 antibody testing detecting the presence of tubal factor infertility. Combining CHSP60 antibody with antibody testing for C. trachomatis has an excellent positive likelihood ratio of 10 for the detection of C. trachomatis-associated tubal factor infertility. CONCLUSION(S) CHSP60 antibody testing is a more accurate test than antibody testing for C. trachomatis for predicting chlamydia-associated tubal factor infertility. These tests, when used in combination at initial infertility evaluation, would provide a rapid noninterventive means of diagnosing tubal factor infertility.

2,4-Dichlorophenoxyacetic acid residues in semen of Ontario farmers

Although paternal exposures to environmental toxicants probably play a role in adverse pregnancy outcomes, few data are available on the extent of this exposure. One semen and two 24-h urine samples were collected from 97 Ontario farmers who had recently used the phenoxy herbicides 2,4-D (2.4-dichlorophenoxyacetic acid) and/or MCPA ([4-chloro-2-methylphenoxyl acetic acid). Both samples were analyzed for 2,4-D using an immunoassay-based technique. Approximately 50% of the semen samples had detectable levels of 2, 4-D (> or =5.0 pph (ng/mL)). Semen levels of 2.4-D were correlated more closely with the second of the two urine samples. Although several studies have measured 2.4-D in the urine of applicators, this study is the first to attempt to measure 2,4-D levels in semen. As these pesticides can be excreted in the semen, they could be toxic to sperm cells and be transported to the woman and developing embryo/fetus. Further research is needed to understand how pesticide handling practices can affect semen pesticide residues and the relationship between the levels observed and reproductive health.

Natural cycle in vitro fertilization-embryo transfer at the University of Ottawa: an inefficient therapy for tubal infertility *

OBJECTIVE To describe our experience with natural cycle IVF making clinical and endocrine comparisons with our standard stimulated cycle IVF program. DESIGN We attempted 75 natural IVF-ET cycles with hCG given to preempt the LH surge and compared these with 450 attempts at standard superovulation IVF-ET done in our unit during the same time period. PATIENTS Natural cycle patients are normally ovulating women < age 38. Superovulation IVF-ET patients are all < 41 years old. Patients in both groups had partners with normal semen parameters and tubal factor infertility. MAIN OUTCOME MEASURES Cancellation rates, pregnancy rates per egg retrieval, per ET procedure, and luteal phase E2:P ratios of the treatment cycles are compared. RESULTS There were 35 of 75 (47%) natural cycle and 112 of 450 (25%) superovulation cycle cancellations. An egg was retrieved in only 24 of 40 (60%) natural cycles and 336 of 338 (99%) superovulation egg retrieval procedures. Pregnancy rates per ovum pick-up procedure were significantly higher: 65 of 338 (19%) in the superovulation versus 2 of 40 (5%) in the natural cycle groups. Pregnancy rates per ET were not significantly different between natural IVF-ET, 2 of 18 (11%) and superovulation IVF-ET, 65 of 298 (22%). The E2:P ratios 5 days after ET were similar in both groups at 18 +/- 4 after natural IVF-ET and 21 +/- 18 after superovulation IVF-ET. CONCLUSIONS [1] Cancellation rates for natural cycle IVF are very high. [2] Midluteal E2:P ratios are the same in both groups. [3] Pregnancy rates per egg retrieval are significantly lower for natural versus superovulation IVF-ET. [4] In our experience, natural cycle IVF-ET is an inefficient therapy for tubal infertility compared with superovulation IVF-ET.

Ovulation induction in polycystic ovary syndrome.

OBJECTIVE To review current non-pharmacologic and pharmacologic options for ovulation induction in women with polycystic ovary syndrome (PCOS). OPTIONS This guideline reviews the evidence for the various options for ovulation induction in PCOS. OUTCOMES Ovulation, pregnancy and live birth rates, risks, and side effects are the outcomes of interest. EVIDENCE Published literature was retrieved through searches of Medline using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and of health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The evidence gathered was reviewed and evaluated by the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was quantified using the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS Benefits include weight reduction and improvements in ovulation, pregnancy, and live birth rates. Potential harms include medication side effects and multiple pregnancies. VALIDATION These guidelines have been reviewed and approved by the Reproductive Endocrinology and Infertility Committee of the SOGC. SPONSOR The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS 1. Weight loss, exercise, and lifestyle modifications have been proven effective in restoring ovulatory cycles and achieving pregnancy in overweight women with PCOS and should be the first-line option for these women. (II-3A) Morbidly obese women should seek expert advice about pregnancy risk. (III-A) 2. Clomiphene citrate has been proven effective in ovulation induction for women with PCOS and should be considered the first-line therapy. Patients should be informed that there is an increased risk of multiple pregnancy with ovulation induction using clomiphene citrate. (I-A) 3. Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.(I-A) Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity. (I-A) 4. Gonadotropin should be considered second-line therapy for fertility in anovulatory women with PCOS. The treatment requires ultrasound and laboratory monitoring. High costs and the risk of multiple pregnancy and ovarian hyperstimulation syndrome are drawbacks of the treatment. (II-2A) 5. Laparoscopic ovarian drilling may be considered in women with clomiphene-resistant PCOS, particularly when there are other indications for laparoscopy. (I-A) Surgical risks need to be considered in these patients. (III-A) 6. In vitro fertilization should be reserved for women with PCOS who fail gonadotropin therapy or who have other indications for IVF treatment. (II-2A).

High rates of perforation are found in endovaginal ultrasound probe covers before and after oocyte retrieval for in vitro fertilization-embryo transfer.

ObjectivesTo study perforation rates of sterile transvaginal ultrasound probe covers before and after oocyte retrieval (OPU) in an IVF-ET program.MethodsTransvaginal ultrasound probe sheaths from two different manufacturers were studied, Cook Innoray (Cook-Canada #TTUPS-100) and Swemed Lab (Frolunda Sweden #715). After controlled ovarian stimulation, OPU was done using the needle guide of a sterile sheathed 5-MHz transvaginal ultrasound transducer (ATL Bothell, Washington, USA). A newer designed Cook probe cover supplied by the manufacturer was also tested after the company was made aware of our initial perforation results. Following each OPU, probe covers were examined for perforations by filling them with water and checking for leaks. If perforations were found, the vaginal transducer was disinfected by soaking for 20 min in 2% gluteraldehyde (Formac®).Twenty unused sterile probe covers from each manufacturer were also tested for perforations.ResultsAfter OPU we found 10/13 (75%) old Cook, and 35/43 (81%) Swemed probe covers to be perforated (NS). Only 5/20 (25%) of the new design Cook probe covers were perforated post OPU (P =0.000005). Analysis of unused probe covers revealed 13/20 (65%) Cook, and 5/20 (25%) Swemed probe covers to be perforated (P =0.02). None of 10 new design unused Cook probe covers were perforated before use.ConclusionsSterile transvaginal ultrasound probe covers have a very high rate of perforation even before use. It is important to examine probe covers for perforations after OPU procedures and to disinfect them as necessary to avoid the risk of sexually transmitted disease. Quality control between brands seems to vary and efforts should be made to develop a cooperative relationship with manufacturers to improve design and quality control in production of ultrasound probe covers used for IVF procedures.

Does serologic evidence of remote Chlamydia trachomatis infection and its heat shock protein (CHSP 60) affect in vitro fertilization-embryo transfer outcome? * †

OBJECTIVE To examine IVF-ET outcome in patients with and without serologic evidence of Chlamydia trachomatis infection and chlamydia heat shock protein 60 (CHSP 60) antibodies. DESIGN Retrospective case control. SETTING University-affiliated IVF-ET program. MAIN OUTCOME MEASURES A total of 195 IVF-ET patients with tubal factor infertility underwent oocyte pick-up, 166 of these women had ET resulting in a total of 37 pregnancies. Serum antibody testing for evidence of remote C. trachomatis and CHSP 60, as well as pregnancy outcome, were determined for all patients. RESULTS There were no differences in pregnancy rates or outcomes between C. trachomatis seropositive versus seronegative groups: 27/118 (23%) C. trachomatis seropositive versus 10/77 (13%) C. trachomatis seronegative patients achieved pregnancy per oocyte pick-up. Pregnancy rates per ET were 27/105 (26%) in C. trachomatis seropositive versus 10/61 (16%) C. trachomatis seronegative patients. In the C. trachomatis positive subgroup, significantly higher pregnancy rates were found in the CHSP 60 antibody positive patients: 24/67 (36%) CHSP 60 positive versus 3/51 (6.0%) CHSP 60 negative patients were pregnant after oocyte pick-up (OR = 8.9, 95% CI = 2.3 to 27.5). Pregnancy rates per ET were 24/57 (42%) in CHSP 60 positive versus 3/48 (7%) CHSP 60 negative patients (OR = 10.9, 95% CI = 2.8 to 33.6). There were no significant differences in any group when examining the following pregnancy outcomes: spontaneous abortion, ectopic pregnancy, preterm and multiple pregnancy rates. CONCLUSIONS [1] There are no differences in pregnancy rates or outcomes in patients with and without serologic evidence of previous C. trachomatis infections. [2] In women seropositive for C. trachomatis, significantly higher pregnancy rates are found in women who are CHSP 60 antibody positive versus negative. [3] Pregnancy outcomes do not appear to be different between these groups.