A multicentre randomized controlled trial of expectant management versus IVF in women with Fallopian tube patency.

BACKGROUND: Although observational studies suggest that IVF is more effective than no treatment for women with Fallopian tube patency, this has not been tested rigorously in a randomized controlled trial (RCT). METHODS: Eligible consenting couples planning their first treatment cycle in five Canadian fertility clinics received either IVF, within 90 days of randomization, or a period of 90 days with no treatment. Random allocation was stratified by female age and sperm quality, and administered using numbered, opaque, sealed envelopes. Follow-up assessed live birth and associated morbidity. RESULTS: Sixty-eight couples were randomized to a first cycle of IVF and 71 couples had 3 months without treatment. The live birth rates were 20/68 (29%) and 1/71 (1%), respectively. The single delivery in the untreated group was of twins, as were six of the 20 IVF deliveries (30%). An average of 2.0 embryos were transferred and no triplet pregnancies resulted. The relative likelihood of delivery after allocation to IVF was 20.9-fold higher than after allocation to no treatment [95% confidence interval (CI) 2.8-155]. The presence of abnormal sperm did not reduce this likelihood. Treating four women (95% CI 3-6) with one cycle of IVF is required to achieve a single additional birth. CONCLUSIONS: This study provides a valid and up-to-date comparison for policy makers and patients as they make choices around IVF, accurately measuring and confirming a major benefit from treatment.

Chronic cough and infertility: a report of two cases.

OBJECTIVE: To report two cases of infertility caused by primary ciliary dyskinesia in patients who presented with an associated complaint of a chronic cough. DESIGN: Case report. SETTING: University teaching hospital. PATIENT(S): Two patients presenting with unexplained infertility and an associated history of long-term chronic cough. INTERVENTION(S): Patients underwent a nasal mucosal biopsy by an otolaryngologist. Electron microscopy (EM) examination of biopsy specimens was performed. MAIN OUTCOME MEASURE(S): Diagnosis and appropriate treatment for functional tubal factor infertility. RESULT(S): Both patients were diagnosed with primary ciliary dyskinesia based on EM of the nasal biopsy specimens. Given this diagnosis, they immediately underwent IVF-ET. Both patients became pregnant with their first IVF-ET cycle. CONCLUSION(S): Other investigators have shown that almost 20% of patients with a chronic cough will have EM evidence of ciliary dyskinesia. Patients presenting with idiopathic infertility and an associated unexplained chronic cough should be referred for nasal biopsy with EM evaluation to rule out primary ciliary dyskinesia. Infertility in these cases, which is due to a functional tubal factor, is best treated with IVF-ET rather than superovulation and intrauterine insemination treatments.

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.

Intracellular pH regulation in human preimplantation embryos.

We report here that intracellular pH (pH(i)) in cleavage-stage human embryos (2-8-cell) is regulated by at least two mechanisms: the HCO(3)(-)/Cl(-) exchanger (relieves alkalosis) and the Na(+)/H(+) antiporter (relieves acidosis). The mean pH(i) of cleavage-stage embryos was 7.12 +/- 0.008 (n = 199) with little variation between different stages. Embryos demonstrated robust recovery from alkalosis that was appropriately Cl(-)-dependent, indicating the presence of the HCO(3)(-)/Cl(-) exchanger. This was further confirmed by measuring the rate of intracellular alkalinization upon Cl(-) removal, which was markedly inhibited by the anion transport inhibitor, 4,4'-diisocyanatostilbene-2,2'-disulphonic acid, disodium salt. The set-point of the HCO(3)(-)/Cl(-) exchanger was between pH(i) 7.2 and 7.3. Embryos also exhibited Na(+)-dependent recovery from intracellular acidosis. Na(+)/H(+) antiporter activity appeared to regulate recovery up to about pH(i) 6.8; this recovery was HCO(3)(-)-independent and amiloride-sensitive, with a pH(i) set-point of approximately 6.8-6.9. A second system that was both Na(+)- and HCO(3)(-)-dependent appeared to mediate further recovery from acidosis up to about pH(i) 7.1. Thus, pH(i) of early human preimplantation embryos appears to be regulated by opposing mechanisms (HCO(3)(-)/Cl(-) exchanger, Na(+)/H(+) antiporter, and possibly a third acid-alleviating transporter that was both Na(+)- and HCO(3)(-)-dependent) resulting in the maintenance of pH(i) within a narrow range.

Glycine transport by single human and mouse embryos.

Mouse zygotes and early cleavage-stage embryos have previously been shown to utilize glycine as an organic osmolyte, accumulating it to oppose any decrease in cell volume. Such glycine uptake in early cleavage-stage mouse embryos is via the glycine-specific Gly transporter. Mouse embryos also possess swelling-activated channels which function to release osmotically active glycine and other osmolytes when cell volume becomes too large. In this study it was found that human cleavage-stage embryos also transported glycine via a similarly saturable, sarcosine-inhibitable transporter, implying that the Gly transporter also mediates glycine transport in human embryos. Mouse zygotes have previously been shown to accumulate more intracellular glycine when cultured at increased osmolarities for 24 h. It was found in the current study that this ability was lost as preimplantation mouse embryo development proceeded, and that early cleavage-stage human embryos may also be capable of such osmosensitive accumulation of glycine. Finally, using spare human eggs which had failed to fertilize or cleave, the presence of swelling-activated currents resembling those in mouse zygotes was demonstrated. These data indicate that osmoregulation in early human embryos occurs via similar mechanisms as in the mouse.

Comparison of serum progesterone as an indicator of pregnancy nonviability in spontaneously pregnant emergency room and infertility clinic patient populations.

OBJECTIVE: To compare the predictive value of serum progesterone in identifying nonviable pregnancy in symptomatic spontaneously pregnant emergency department patients and asymptomatic patients attending an infertility clinic. DESIGN: Retrospective study. SETTING: Tertiary-care academic health center. PATIENT(S): One hundred thirty-seven pregnant patients who presented to the emergency department for whom clinical outcomes were available, and 123 consecutive patients who became pregnant during treatment at the infertility clinic. INTERVENTION(S): Serum progesterone measurement. MAIN OUTCOME MEASURE(S): The sensitivity, specificity, and predictive value of serum progesterone <45 nmol/L in identifying nonviable pregnancies were determined for each of the groups. RESULT(S): Sensitivity and specificity of serum progesterone <45 nmol/L in predicting nonviable pregnancies were 88.6% and 87.5%, respectively, in spontaneously pregnant patients who presented to the emergency department with pain or bleeding and 58.8% and 100% in infertility patients who had undergone controlled ovarian hyperstimulation for in vitro fertilization or intrauterine insemination. Sensitivity and specificity for all other infertility clinic patients were variable. CONCLUSION(S): The predictive value of low serum progesterone in identifying nonviable pregnancies varies with patient populations.

Polycystic ovary disease and the risk of pregnancy-induced hypertension.

OBJECTIVE: To compare the incidence of pregnancy-induced hypertension in patients with and without polycystic ovary disease (PCOD). STUDY DESIGN: We conducted a retrospective, case-control analysis of patients who achieved singleton pregnancies with human menopausal gonadotropin (hMG) therapy. Twenty-two PCOD patients were compared to 27 infertility patients without PCOD who were pregnant after hMG therapy. Non-PCOD patients received hMG for superovulation as part of superovulation/intrauterine insemination or in vitro fertilization/embryo transfer. PCOD patients were receiving hMG for simple ovulation induction. Pregnancy-induced hypertension was defined as late pregnancy blood pressure > 140/90 mm Hg on two readings six hours apart and return to normal blood pressure by four to six weeks postpartum. RESULTS: There were no differences between PCOD and non-PCOD patients with reference to age, body mass index, parity or other pregnancy-induced hypertension risk factors (i.e., chronic hypertension, diabetes or chronic renal disease). Pregnant PCOD patients had a much higher incidence of pregnancy-induced hypertension, 31.8% (7/22), versus non-PCOD patients, who only had a pregnancy-induced hypertension incidence of 3.7% (1/27) (P = .016, OR = 12.1, 95% CI = 1.3-566.8). CONCLUSION: PCOD patients are at very high risk of pregnancy-induced hypertension when pregnant after ovulation induction.

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.

Uterine artery embolization--a successful treatment to control bleeding cervical pregnancy with a simultaneous intrauterine gestation.

A case of a woman suffering from a bleeding heterotopic cervical pregnancy is described. The concurrent cervical pregnancy and intrauterine gestation were diagnosed by ultrasound and bleeding was initially controlled with selective fluoroscopic uterine artery embolization. A selective fetal reduction was done with ultrasound-guided intracardiac potassium chloride. Uterine artery embolization has been used successfully to control haemorrhage in cervical pregnancies when the main goal was to allow preservation of the uterus, thus maintaining potential fertility. This is the first report of arterial embolization used to control bleeding for maintaining a concurrent intrauterine heterotopic pregnancy in an in-vitro fertilization patient. Unfortunately, subsequent conservative measures led to undesired outcome. This procedure initially controlled the bleeding without disrupting the intrauterine fetal cardiac activity.

Serum progesterone in predicting pregnancy outcome after assisted reproductive technology.

PURPOSE: Our purpose was to determine whether serum progesterone predicts pregnancy outcome after superovulation. METHODS: One hundred twenty-three consecutively pregnant patients were divided into three groups: group I, 55 patients following superovulation for assisted reproductive technologies; group II, 23 patients after correction of oligoovulation; and group III, 45 patients who conceived spontaneously. When beta-human chorionic gonadotropin was positive, progesterone was measured on the same serum sample. A serum progesterone level of 45 microns/L was set to differentiate between nonviable pregnancy and ongoing pregnancy. RESULTS: In group I, zero (0%) of 38 ongoing pregnancies and 10 (59%) of 17 nonviable pregnancies were observed with a progesterone level of < 45 microns/L [14.2 ng/ml (P < 0.001)]. In group II, 4 (27%) of 15 ongoing pregnancies and 5 (63%) of 8 nonviable pregnancies had a progesterone level of < 45 microns/L (P = NS). In group III, 10 (42%) of 24 ongoing pregnancies and 15 (71%) of 21 nonviable pregnancies were observed with a progesterone level of < 45 microns/L (14.2 ng/ml) (P = NS). CONCLUSIONS: A serum progesterone level of < 45 nM predicts nonviable pregnancy after superovulation for assisted reproductive technology.

Culture with Matrigel inhibits development of mouse zygotes.

PURPOSE: It was reported that Matrigel improved hatching of mouse blastocysts produced in vitro from F1 hybrid-derived zygotes. We investigated whether Matrigel would be similarly beneficial with outbred strain-derived embryos, which exhibit a "two-cell" block similar to the developmental blocks of other species. METHODS: Mouse embryo development was assessed with or without Matrigel in KSOM medium, which supports the development of blocking strain zygotes in vitro, and in human tubal fluid (HTF) medium, which normally does not but which is used for human IVF. RESULTS: Matrigel severely inhibited the development of zygotes to blastocysts in KSOM and did not improve culture in HTF. There was no effect on development from the two-cell stage. We were not able to replicate the previous finding of Matrigel's beneficial effect on hatching of F1-derived zygotes. CONCLUSIONS: Matrigel may be a deleterious addition to embryo culture or coculture systems.

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.

A novel approach to the treatment of ascites associated with ovarian hyperstimulation syndrome.

Ascites is a clinical manifestation of severe ovarian hyperstimulation syndrome (OHSS) which may complicate the induction of ovulation using exogenous gonadotrophins. In severe OHSS severe ascites may occur and can lead to dyspnoea, abdominal discomfort and oliguria. To relieve ascites paracentesis is performed two to three times weekly as needed. We report three cases where an indwelling peritoneal catheter was used to decrease the need for repeated paracentesis. Under ultrasound guidance a closed system Dawson-Mueller catheter with 'simp-loc' locking design was inserted to allow continuous drainage of the ascitic fluid. A total of 23 l of the ascitic fluid were drained from the first, 20 l from the second and 28 l from the third patient with significant decrease in abdominal discomfort and improvement in the urine output. No complications or adverse reactions were noted. Continuous drainage of the ascitic fluid is efficient. It quickly decreases the abdominal discomfort, improves the urine output and prevents the need for multiple abdominal paracenteses which some patients may require.

Diagnosis of Chlamydia trachomatis infections in asymptomatic men and women by PCR assay.

A PCR assay was evaluated for its ability to detect genital chlamydial infection in asymptomatic men and women. Urethral swab specimens were collected from 472 men for culture and PCR assay, and first-void urine (FVU) specimens were collected from 379 of these men for enzyme immunoassay (EIA) and PCR assay. Cervical swab specimens were collected from 242 women for culture, EIA, and PCR assay. Patients were considered infected if they were culture positive or positive by PCR with both plasmid- and major outer membrane protein-based primers. By using this extended "gold standard," the prevalence of infection in this population was 7.6% for men and 7.9% for women. For men, the sensitivities of urethral swab specimen culture and PCR and FVU specimen EIA and PCR were 61, 72, 55, and 91%, respectively. All assays had specificities of > or = 99.8%. The positive and negative predictive values for PCR testing of FVU specimens were 100 and 99.4%, respectively, compared with values of 96.3 and 97.8%, respectively, for PCR of urethral swab specimens. The sensitivities of cervical swab specimen culture and PCR testing were 42 and 90%, respectively, with corresponding specificities of 100 and 99.3%. All cervical swabs were negative by EIA. Molecular techniques such as PCR assays are valuable tools for the detection of symptomatic genital chlamydial infection. In particular, PCR assays of FVU specimens from men offer a highly sensitive, noninvasive screening tool that will likely improve patient compliance for diagnostic testing.

Prevalence of endometriosis in rhesus (Macaca mulatta) monkeys ingesting PCB (Aroclor 1254): review and evaluation.

A total of 80 menstruating rhesus monkeys (Macaca mulatta) were equally and randomly divided among groups receiving 0, 5, 20, 40, or 80 mu g of Aroclor 1254/kg body weight/day during a 6-year toxicological-reproduction study. During the first 3 years of the study, 4 of the treated monkeys became moribund and were euthanized; 3 had endometriosis. This finding suggested a possible link between the PCB treatment and the occurrence of endometriosis. However, neither a laparoscopic examination of the control and high-dose monkeys nor the necropsy data provided evidence for a possible link between the PCB treatment and the observed incidence (37% (6/16) of controls; 25% (16/64) of treated monkeys and/or the severity of the endometrial lesions. Additional clinical and historical data not contained in previous reports are presented to facilitate independent evaluation of the relationship between PCB ingestion and endometriosis. We conclude that the incidence and severity of the endometriosis lesions observed in the rhesus monkeys utilized in this study did not have any relationship with the dosages of Aroclor 1254 they ingested.

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.

Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation syndrome despite mini-dose heparin prophylaxis.

Thromboembolic events are serious but rare complications following ovarian stimulation for in-vitro fertilization (IVF). We report a case of severe ovarian hyperstimulation syndrome (OHSS), presenting in a second IVF cycle with a late complication of right internal jugular vein thrombosis despite mini-dose heparin prophylaxis. Thrombosis and thromboembolism as late complications of OHSS have been reported by others but not after prophylactic heparinization. The patient was successfully treated with heparin and the twin pregnancy is ongoing. In pregnant patients with severe OHSS consideration should be given to treatment with low dose heparin throughout the first trimester to prevent the serious complications of thrombosis and thromboembolism.

Sex ratio of babies is unchanged after transfer of fast- versus slow-cleaving embryos.

PURPOSE: A higher proportion of male offspring has been observed after transferring faster-developing embryos in a number of animal species. Therefore, we evaluated the correlation between the sex ratio of delivered babies and the cleavage stage of transferred embryos in a human IVF-ET program. METHODS: The sex of infants born (n = 104) after transfer of exclusively slower-cleaving < or = 3 cell (n = 41) versus exclusively faster-cleaving > or = 4 cell (n = 63) embryos was compared. Furthermore, all boys and girls resulting from IVF-ET (n = 213) were compared with respect to: the average number of cells in the embryos that were transferred, the embryo with the greatest number of cells in the cohort transferred and the percentage of embryos that were faster cleaving. RESULTS: Thirty seven percent (15/41) of infants resulting from the transfer of exclusively slower-growing embryos were girls and 38% (24/36) of the infants from the faster-growing embryos were girls (NS). The analysis all 213 babies born after 145 embryo transfer procedures did not suggest any differences in embryo cleavage rates in embryo transfers leading to male versus female infants. CONCLUSIONS: A greater number of boys born was not observed after transfer of faster-cleaving embryos as has been described in other animal species. The race to be male may not occur until later cleavage divisions or may not occur in the human embryo.