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Abstract Objective To compare the effectiveness of an electrocautery strategy with ovulation induction using recombinant follicle stimulating hormone in patients with clomiphene resistant polycystic ovary syndrome. Design Randomised controlled trial. [...]

Methotrexate is not necessarily cheaper than laparoscopic salpingostomy in treating tubal pregnancy. A tubal pregnancy occurs when the embryo does not reach the uterus but attaches inside the fallopian tubes.

In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse.

Tubal ectopic pregnancy can be surgically treated by salpingectomy, in which the affected Fallopian tube is removed, or salpingotomy, in which the tube is preserved. Despite potentially increased risks of persistent trophoblast and repeat ectopic pregnancy, salpingotomy is often preferred over salpingectomy because the preservation of both tubes is assumed to offer favourable fertility prospects, although little evidence exists to support this assumption. We aimed to assess whether salpingotomy would improve rates of ongoing pregnancy by natural conception compared with salpingectomy.

A randomized, controlled, multicenter clinical study conducted in women with poor ovarian response and undergoing in vitro fertilisation (IVF)intracytoplasmic sperm injection (ICSI).

Data on the concentrations of didanosine (ddI) and tenofovir (TFV) in seminal plasma are sparse. Subtherapeutic drug concentrations within the lumen of the male genital tract may have implications for selection and transmission of drug-resistant HIV strains. On the other hand, sufficient penetration of these drugs into the male genital tract has potential toxic effects on the spermatozoa and their precursors. In the current study, the authors obtained paired semen and blood samples at variable time points after drug intake from 30 HIV-1-infected patients using a ddI (n = 15) or ddI + TFV (n = 15) containing an antiretroviral regimen. Didanosine and TFV concentrations were measured in seminal and blood plasma and semen quality was assessed. Both ddI and TFV penetrated well into seminal plasma. Whereas blood plasma ddI concentrations dropped to near or below the lower limit of quantification of 0.017 μg/mL 9 hours after drug intake, the ddI concentration in seminal plasma remained detectable during the whole dosing interval with a median of 0.20 and 0.21 μg/mL in the ddI and ddI + TFV groups, respectively. Tenofovir was detectable during the whole dosing interval in both blood and seminal plasma with a median concentration of 0.12 and 0.25 μg/mL, respectively, and a median seminal-to-blood-plasma ratio of 3.3. Semen quality was within the normal range according to the criteria of the World Health Organization, except for the percentage of progressively motile sperm, which was low in both groups of patients. The authors conclude that ddI and TFV penetrate well into seminal plasma and that the reduced sperm motility deserves further study.

OBJECTIVE: To compare reproductive outcomes in couples carrying a structural chromosome abnormality and non-carrier couples referred for chromosome analysis after two or more miscarriages. Design Case-control study. Setting Six centres for clinical genetics in the Netherlands. Participants 278 carrier couples and 427 non-carrier couples referred for chromosome analysis between 1992 and 2000 after two or more miscarriages before 20 weeks of gestation. Couples were followed up for at least 24 months after chromosome analysis. MAIN OUTCOME MEASURES: The birth of at least one healthy child, at least one more miscarriage, and viable offspring with unbalanced chromosomal abnormalities after parental chromosome analysis. RESULTS: Mean follow-up after chromosome analysis was 5.8 years. 120 of 247 (49%) carrier couples had one or more miscarriage after chromosome analysis compared with 122 of 409 (30%) non-carrier couples (difference 19%, 95% confidence interval 11% to 26%; P < 0.01). The percentage of couples with at least one healthy child was not significantly different in carrier couples (83%) and non-carrier couples (84%) (difference -1%, - 7% to 5%). Among 550 pregnancies in carrier couples, two viable unbalanced chromosome abnormalities were detected at prenatal diagnosis (0.4%) and the fetuses aborted and two children with an unbalanced karyotype were born (0.4%). CONCLUSIONS: Couples whose carrier status was ascertained after two or more miscarriages have a low risk of viable offspring with unbalanced chromosomal abnormalities. Their chances of having a healthy child are as high as non-carrier couples, despite a higher risk of miscarriage.

OBJECTIVE: To identify additional factors, such as maternal age or factors related to previous reproductive outcome or family history, and the corresponding probability of carrying a chromosome abnormality in couples with two or more miscarriages. Design Nested case-control study. Setting Six centres for clinical genetics in the Netherlands. Participants Couples referred for chromosome analysis after two or more miscarriages in 1992-2000; 279 carrier couples were marked as cases, and 428 non-carrier couples served as controls. MAIN OUTCOME MEASURES: Independent factors influencing the probability of carrier status and the corresponding probability of carrier status. RESULTS: Four factors influencing the probability of carrier status could be identified: maternal age at second miscarriage, a history of three or more miscarriages, a history of two or more miscarriages in a brother or sister of either partner, and a history of two or more miscarriages in the parents of either partner. The calculated probability of carrier status in couples referred for chromosome analysis after two or more miscarriages varied between 0.5% and 10.2%. CONCLUSIONS: The probability of carrier status in couples with two or more miscarriages is modified by additional factors. Selective chromosome analysis would result in a more appropriate referral policy, could decrease the annual number of chromosome analyses, and could therefore lower the costs.

The aetiology of impaired spermatogenesis is unknown in the majority of subfertile men. From several studies of concordance for involuntary childlessness among men, we can conclude that there is a substantial familial component in male subfertility and that shared loci segregating through families can be assumed. We now know that deletions on the Y chromosome, which do not penetrate fully, account for some of these cases. There are good reasons to suspect that other cases result from mutations in genes located elsewhere in the genome. In this article, we discuss different approaches to unravelling the molecular basis of impaired spermatogenesis originating from genetic abnormalities in chromosomes other than the Y chromosome. Genetic mapping studies are in general a good approach to detect disease-causing genes that are segregating through a population; they can provide a shortcut to unravelling the biochemistry of a disease. In this paper, we explain our reasons for arguing that linkage and association studies are no promising means to identify the genes causing impaired spermatogenesis. We conclude that direct screening of candidate genes for mutations will be necessary to detect genes involved in impaired spermatogenesis. However, this approach requires studies of the biochemical pathways of normal and abnormal spermatogenesis. Since we have a poor understanding of these pathways, more research is needed into the biochemistry of spermatogenesis.

In this study, we compare the prognostic significance of hysterosalpingography (HSG) and laparoscopy for fertility outcome. In a prospective cohort study in 11 clinics participating in the Canadian Infertility Treatment Evaluation Study (CITES), consecutive couples who registered between 1 April 1984 and 31 March 1987 for the evaluation of subfertility and who underwent HSG and laparoscopy were included. Unilateral and bilateral tubal occlusion at HSG and laparoscopy were related to treatment-independent pregnancy. Cox regression was used to calculate fecundity rate ratios (FRR). Of the 794 patients who were included, 114 (14%) showed one-sided tubal occlusion and 194 (24%) showed two-sided tubal occlusion on HSG. At laparoscopy, 94 (12%) showed one-sided tubal occlusion and 96 (12%) showed two-sided tubal occlusion. Occlusion detected on HSG and laparoscopy showed a moderate agreement beyond chance (weighted κ-statistic 0.42). The adjusted FRR of one-sided tubal occlusion at HSG was 0.80, whereas two-sided tubal occlusion showed an FRR of 0.49. For laparoscopy, the FRR were 0.51 and 0.15 respectively. After a normal or one-sided occluded HSG, laparoscopy showed two-sided occlusion in 5% of the patients, and fertility prospects in these patients were virtually zero. If two-sided tubal occlusion was detected on HSG but not during laparoscopy, fertility prospects were slightly impaired. Fertility prospects after a two-sided occluded HSG were strongly impaired in cases where laparoscopy showed one-sided and two-sided occlusion, with FRR of 0.38 and 0.19 respectively. Although laparoscopy performed better than HSG as a predictor of future fertility, it should not be considered as the perfect test in the diagnosis of tubal pathology. For clinical practice, laparoscopy can be delayed after normal HSG for at least 10 months, since the probability that laparoscopy will show tubal occlusion after a normal HSG is very low.

Current algorithms for the diagnosis of ectopic pregnancy do not take into account the heterogeneity in patient profiles. Such heterogeneity can lead to differences in the pre-test probability of ectopic pregnancy. In patients with clinical symptoms, for example, the probability of presence of an ectopic pregnancy is higher than in symptom-free patients. Any additional tests should then be interpreted differently, depending on the pre-test probability. We present a diagnostic algorithm that uses probabilistic decision rules for the evaluation of women with suspected ectopic pregnancy with flexible cut-off levels for test positivity We compare it with a general algorithm that uses fixed cut-off levels. Fictitious cohorts, varying in prevalence of ectopic pregnancy were put together, using data obtained from a cohort of >800 women with suspected ectopic pregnancy. In the inflexible algorithm, ectopic pregnancy was diagnosed whenever it could be visualized at transvaginal sonography, or where serum human chorionic gonadotrophin (HCG) exceeded a rigid cut-off level; ectopic pregnancy was rejected if an intrauterine pregnancy was seen or when serum HCG decreased. In the flexible algorithm, a post-test probability was obtained after each test, using pre-test probabilities and test-based likelihood ratios. Ectopic pregnancy was diagnosed whenever the post-test probability for ectopic pregnancy exceeded 95%, whereas this diagnosis was rejected if the calculated post-test probability fell below 1%. For both algorithms, sensitivity and specificity as well as predictive values were calculated. At each prevalence, the inflexible algorithm was associated with a sensitivity of 93% and a specificity of 97%. In contrast, the sensitivity and specificity of the flexible, individualized algorithm depended on the prevalence of ectopic pregnancy. Consequently, predictive values varied strongly when the inflexible algorithm was used, whereas they were much more stable after using the flexible algorithm. For five possible valuations of false positive and false negative diagnoses, the flexible algorithm reduced the expected disutility, compared with the inflexible algorithm. It is concluded that clinicians should incorporate probabilistic decision rules in algorithms used for the diagnosis of ectopic pregnancy.

Current algorithms for the diagnosis of ectopic pregnancy do not take into account the heterogeneity in patient profiles. Such heterogeneity can lead to differences in the pre-test probability of ectopic pregnancy. In patients with clinical symptoms, for example, the probability of presence of an ectopic pregnancy is higher than in symptom-free patients. Any additional tests should then be interpreted differently, depending on the pre-test probability. We present a diagnostic algorithm that uses probabilistic decision rules for the evaluation of women with suspected ectopic pregnancy with flexible cut-off levels for test positivity We compare it with a general algorithm that uses fixed cut-off levels. Fictitious cohorts, varying in prevalence of ectopic pregnancy were put together, using data obtained from a cohort of >800 women with suspected ectopic pregnancy. In the inflexible algorithm, ectopic pregnancy was diagnosed whenever it could be visualized at transvaginal sonography, or where serum human chorionic gonadotrophin (HCG) exceeded a rigid cut-off level; ectopic pregnancy was rejected if an intrauterine pregnancy was seen or when serum HCG decreased. In the flexible algorithm, a post-test probability was obtained after each test, using pre-test probabilities and test-based likelihood ratios. Ectopic pregnancy was diagnosed whenever the post-test probability for ectopic pregnancy exceeded 95%, whereas this diagnosis was rejected if the calculated post-test probability fell below 1%. For both algorithms, sensitivity and specificity as well as predictive values were calculated. At each prevalence, the inflexible algorithm was associated with a sensitivity of 93% and a specificity of 97%. In contrast, the sensitivity and specificity of the flexible, individualized algorithm depended on the prevalence of ectopic pregnancy. Consequently, predictive values varied strongly when the inflexible algorithm was used, whereas they were much more stable after using the flexible algorithm. For five possible valuations of false positive and false negative diagnoses, the flexible algorithm reduced the expected disutility, compared with the inflexible algorithm. It is concluded that clinicians should incorporate probabilistic decision rules in algorithms used for the diagnosis of ectopic pregnancy.

Background. Laparoscopy has generally replaced open surgery in the treatment of ectopic pregnancy. This study assesses the impact of the introduction of laparoscopy in the surgical treatment of tubal pregnancy on costs.Methods. Consecutive patients undergoing primary surgery for tubal pregnancy between January 1992 and December 1995 were included in the study. Surgery was performed laparo-scopically or by open surgery. Cost for each treatment was calculated by multiplying resources used with calculated resource unit prices. The analysis was stratified for radical and conservative surgery.Results. Data of 255 patients were analysed. Tubal pregnancy was successfully treated in all patients. Costs per patient were US$ 3,490 for radical open surgery, US$ 1,872 for radical laparoscopic surgery, US$ 3,420 for conservative open surgery and US$ 2,125 for conservative laparoscopic surgery. Differences in costs were caused by a decreased duration of hospital stay after laparoscopy, and, in case of conservative surgery, by an increased persistent tropho-blast rate after laparoscopy.Conclusions. Laparoscopy is equally effective as open surgery in the treatment of tubal pregnancy, and considerably reduces costs

To assess the value of hysterosalpingography (HSG) in diagnosing tubal patency and peritubal adhesions using laparoscopy with chromopertubation as the gold standard.

To evaluate short-term effectiveness of systemic methotrexate (MTX) in interstitial pregnancy.

To review current knowledge on the risk of ectopic pregnancy (EP), with the exception of contraceptive methods.

Objective:To determine the ectopic pregnancy rate among symptom-free women at increased risk undergoing a screening program involving transvaginal sonography and serum hCG testing.

The standard surgical procedure for treatment of tubal ectopic pregnancy is salpingectomy, in which the affected fallopian tube is removed. A feasible alternative intervention, salpingotomy, has been promoted since 1957. With this procedure, the pregnancy is removed while the affected tube is preserved. There are 2 risks associated with salpingotomy: a repeated ectopic pregnancy in the same tube and a persistent trophoblast requiring additional treatment. Despite these potential drawbacks, salpingotomy has been widely used and often preferred over salpingectomy because it has been assumed that preservation of both tubes increased the prospects for a future pregnancy. However, limited data support this assumption, and it remains unclear whether the potential benefits of salpingotomy outweigh the risks.

Ectopic pregnancy occurs in about 1 of pregnant women. This early pregnancy complication may be life-threatening and adversely affect future fertility. The ability to diagnose this condition before it has deteriorated has changed it from a life-threatening disease into a more benign manageable one. This article reviews changes during the past century in the diagnostic and therapeutic management of ectopic pregnancies.

Both in vitro fertilization (IVF) and preimplantation genetic screening are being increasingly used, the latter for women of advanced maternal age. Observational studies show that, when screening is added to IVF, implantation rates increase but rates of ongoing pregnancies do not. Some researchers believe that preimplantation genetic screening of cleavage-stage embryos for aneuploidies may make IVF more effective. The present multicenter, randomized, double blind, controlled trial compared 3 cycles of IVF with embryo selection based either on preimplantation genetic screening or on the morphologic features of the embryo. Of the 408 participants, all women ranging in age from 35 through 41 years, 206 were assigned to preimplantation genetic screening. Screening accompanied 434 of 836 cycles of IVF. Screening began 3 days after follicular aspiration by biopsying a single blastomere on all embryos having 4 or more blastomeres.

Clomiphene citrate (CC), an antiestrogen, is first-line treatment for polycystic ovary syndrome (PCOS), but up to one fourth of treated women fail to ovulate. Induction with gonadotropins is an option in CC-resistant women but is costly, requires extensive monitoring, and entails a risk of multiple pregnancies. Another option, laparoscopic electrocautery of the ovaries, causes minimal morbidity, precludes the need to monitor cycles, and has a low risk of multiple pregnancies. In this prognostic study, 83 women having CC-resistant PCOS who were participating in a randomized multicenter trial underwent laparoscopic electrocautery, followed by CC if anovulation persisted. Treatment failure was defined as lack of ovulation within 8 weeks after the procedure or lack of an ongoing pregnancy with or without CC treatment. Ovarian volume was estimated by transvaginal ultrasonography.

(Abstracted from Lancet2018;391:758–765)Clomifene citrate has long been used as a first-line ovulation induction agent for women wishing to conceive who have normogonadotropic anovulation (absent or irregular ovulation). Women who ovulate but do not conceive after several cycles with clomifene citrate are usually switched to ovulation induction with gonadotrophins, with or without intrauterine insemination.

(Abstracted from N Engl J Med2016;374:1942–1953)Obesity is a prevalent health condition that affects 14% to 20% of women of reproductive age. Some of the adverse affects of obesity on reproductive health include increased risks of menstrual dysfunction, anovulation, and infertility, especially resulting in failure of assisted reproductive techniques.

Despite intensive investigation, an underlying cause of miscarriage has not been found in a high proportion of women with a history of recurrent miscarriage. No effective intervention has been identified that improves rates of live birth. Some investigators have suggested that treatment of women with unexplained recurrent miscarriage with aspirin and low-molecular-weight heparin may increase the proportion of live births; the limited data available from randomized controlled trials have been inconsistent.

It is expected that, as women continue to postpone childbearing, more of them will present to fertility centers with age-related subfertility. The most widely used measure of ovarian reserve is the basal blood level of follicle-stimulating hormone (FSH) in the early follicular phase of the cycle. Its predictive value seems limited in the setting of in vitro fertilization, and its value for screening a general subfertile population is not clear. This prospective cohort study, carried out at 19 fertility centers in the Netherlands, enrolled subfertile ovulatory women lacking 2-sided tubal pathology whose partners had normal sperm parameters. The fertility workup included an estimate of basal FSH on cycle day 3. The study population consisted of 3270 consecutive couples followed up at 12 months, 562 of whom (16%) had a spontaneous ongoing pregnancy. Four of these were multiple pregnancies. Another 61 couples had unsuccessful pregnancies.

Mitotic errors during early development of human preimplantation embryos are common, rendering a large proportion of embryos chromosomally mosaic. It is also known that the percentage of diploid cells in human diploid-aneuploid mosaic embryos is higher at the blastocyst than at the cleavage stage. In this study, we examined whether there is temporal and/or developmental-stage variation in the occurrence of mitotic errors in human preimplantation embryos from the first day of development onward using mitotically stable digynic tripronuclear human embryos as a model system. All the cells of the 114 digynic tripronuclear human preimplantation embryos included were analyzed by fluorescence in situ hybridization for chromosomes 1, 13, 16, 17, 18, 21, X, and Y. Embryos were grouped according to day of development (1–6) and developmental stage (2-cell to blastocyst stage). The possibility of a mitotic error was highest in the first and second mitotic divisions. The percentage of cells with mitotic errors increased during preimplantation development and was highest at the 9–16 cell stage (76%, P= 0.027). Thereafter, the percentage of cells with mitotic errors decreased to 64% at the morula and 56% at the blastocyst stage. The pattern found correlates with the activation of the embryonic genome at the 8–16 cell stage. A better insight in the timing of occurrence of mitotic errors in human preimplantation embryos could help in understanding and prevention of these errors and is relevant in the context of PGS.

OBJECTIVE: To evaluate the effectiveness of 15 minutes of immobilisation versus immediate mobilisation after intrauterine insemination. Design Randomised controlled trial. Setting One academic teaching hospital and six non-academic teaching hospitals. Participants Women having intrauterine insemination for unexplained, cervical factor, or male subfertility. Interventions 15 minutes of immobilisation or immediate mobilisation after insemination. MAIN OUTCOME MEASURE: Ongoing pregnancy per couple. RESULTS: 391 couples were randomised; 199 couples were allocated to 15 minutes of immobilisation after intrauterine insemination, and 192 couples were allocated to immediate mobilisation (control). The ongoing pregnancy rate per couple was significantly higher in the immobilisation group than in the control group: 27% (n=54) versus 18% (34); relative risk 1.5, 95% confidence interval 1.1 to 2.2 (crude difference in ongoing pregnancy rates: 9.4%, 1.2% to 17%). Live birth rates were 27% (53) in the immobilisation group and 17% (32) in the control group: relative risk 1.6, 1.1 to 2.4 (crude difference for live birth rates: 10%, 1.8% to 18%). In the immobilisation group, the ongoing pregnancy rates in the first, second, and third treatment cycles were 10%, 10%, and 7%. The corresponding rates in the mobilisation group were 7%, 5%, and 5%. CONCLUSION: In treatment with intrauterine insemination, 15 minutes’ immobilisation after insemination is an effective modification. Immobilisation for 15 minutes should be offered to all women treated with intrauterine insemination. Trial registration Current Controlled Trials ISRCTN53294431.

Analyses of recent literature and theoretical cost evaluations have suggested that administration of systemic methotrexate to treat patients with tubal pregnancy is more cost-effective than surgical treatment with laparoscopic salpingostomy. This study was conducted to evaluate the two methods of treatment in actual clinical settings with an emphasis on economic comparison.