Total motile sperm count: a better indicator for the severity of male factor infertility than the WHO sperm classification system.

STUDY QUESTION: Does the prewash total motile sperm count (TMSC) have a better predictive value for spontaneous ongoing pregnancy (SOP) than the World Health Organization (WHO) classification system? SUMMARY ANSWER: The prewash TMSC shows a better correlation with the spontaneous ongoing pregnancy rate (SOPR) than the WHO 2010 classification system. WHAT IS KNOWN ALREADY: According to the WHO classification system, an abnormal semen analysis can be diagnosed as oligozoospermia, astenozoospermia, teratozoospermia or combinations of these and azoospermia. This classification is based on the fifth percentile cut-off values of a cohort of 1953 men with proven fertility. Although this classification suggests accuracy, the relevance for the prognosis of an infertile couple and the choice of treatment is questionable. The TMSC is obtained by multiplying the sample volume by the density and the percentage of A and B motility spermatozoa. STUDY DESIGN, SIZE, DURATION: We analyzed data from a longitudinal cohort study among unselected infertile couples who were referred to three Dutch hospitals between January 2002 and December 2006. Of the total cohort of 2476 infertile couples, only the couples with either male infertility as a single diagnosis or unexplained infertility were included (n = 1177) with a follow-up period of 3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all couples a semen analysis was performed. Based on the best semen analysis if more tests were performed, couples were grouped according to the WHO classification system and the TMSC range, as described in the Dutch national guidelines for male infertility. The primary outcome measure was the SOPR, which occurred before, during or after treatments, including expectant management, intrauterine insemination, in vitro fertilization or intracytoplasmic sperm injection. After adjustment for the confounding factors (female and male age, duration and type of infertility and result of the postcoital test) the odd ratios (ORs) for risk of SOP for each WHO and TMSC group were calculated. The couples with unexplained infertility were used as reference. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 514 couples did and 663 couples did not achieve a SOP. All WHO groups have a lower SOPR compared with the unexplained group (ORs varying from 0.136 to 0.397). Comparing the couples within the abnormal WHO groups, there are no significant differences in SOPR, except when oligoasthenoteratozoospermia is compared with asthenozoospermia [OR 0.501 (95% CI 0.311-0.809)] and teratozoospermia [OR 0.499 (95% CI: 0.252-0.988)], and oligoasthenozoospermia is compared with asthenozoospermia [OR 0.572 (95% CI: 0.373-0.877)]. All TMSC groups have a significantly lower SOPR compared with the unexplained group (ORs varying from 0.171 to 0.461). Couples with a TMSC of <1 × 10(6) and 1-5 × 10(6) have significantly lower SOPR compared with couples with a TMSC of 5-10 × 10(6) [respectively, OR 0.371 (95% CI: 0.215-0.64) and OR 0.505 (95% CI: 0.307-0.832)]. LIMITATIONS, REASON FOR CAUTION: To include all SOPs during the follow-up period of 3 years, couples were not censured at the start of treatment. WIDER IMPLICATIONS OF THE FINDINGS: Roughly, three prognostic groups can be discerned: couples with a TMSC <5, couples with a TMSC between 5 and 20 and couples with a TMSC of more than 20 × 10(6) spermatozoa. We suggest using TMSC as the method of choice to express severity of male infertility. STUDY FUNDING/COMPETING INTERESTS: None.

Predicting dropout in fertility care: a longitudinal study on patient-centredness.

STUDY QUESTION: Are clinic factors, including patients' experiences with patient-centred care, associated with dropout in fertility care? SUMMARY ANSWER: Clinic factors, including patients' experiences with patient-centred care, are not related to dropout. WHAT IS KNOWN ALREADY: In fertility care, a significant proportion of patients do not achieve pregnancy because they discontinue treatment prematurely. Many studies have tried to identify factors predicting dropout, showing incompatible results. However, these studies mainly focus on factors at the treatment and patient level, while clinic factors have received little attention. STUDY DESIGN, SIZE, DURATION: This prospective, longitudinal study was nested within a large RCT, which aims to improve the level of patient-centredness of Dutch fertility care. Of the 1620 infertile women who were invited to participate, the baseline measurement of the study (T0) included 693 women who completed a questionnaire about their experiences with patient-centred fertility care. The follow-up of the patients was 1 year (T1). PARTICIPANTS/MATERIALS, SETTING, METHODS: All included women suffered from infertility and were undergoing treatment in one of the 32 Dutch clinics involved in the trial. Levels of patient-centredness were determined using the Patient-Centredness Questionnaire-Infertility (PCQ-Infertility) at T0. Meanwhile, a professionals' questionnaire was used to gather additional information on characteristics of the clinic (e.g. the number of patients per year or the presence of a fertility nurse). After 1 year, at T1 measurement, patients completed a questionnaire on their current status in fertility care, including their main reason for discontinuation if applicable. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 693 non-pregnant women completed the questionnaire set at T0 and 534 women (77.1%) provided consent for follow-up. At T1 measurement, 434 women (81.3%) completed the questionnaire and 153 of these women (35.2%) continued treatment while 76 women (17.5%) dropped out. Another 175 women (40.3%) had achieved pregnancy and 30 patients (7.9%) were advised to discontinue treatment for medical reasons. Neither levels of patient-centredness nor the additional clinic characteristics differed significantly between dropouts and compliers. However, patients who did not receive assisted reproduction treatment (ART; e.g. underwent intrauterine insemination, IUI) before they dropped out had significantly lower scores on the PCQ-Infertility subscale 'Respect for patients' values' than patients who continued their treatment [odds ratio (OR) 0.57; 95% confidence interval (CI) 0.34-0.95]. Patients who received ART and, subsequently, dropped out had higher scores on the PCQ-Infertility subscale 'Patient involvement' than those receiving non-ART (OR 2.39; 95% CI 1.02-5.59). LIMITATIONS, REASONS FOR CAUTION: We were not able to follow-up a significant proportion (ca. 19%) of the 1620 women who were invited for T0 measurement, which might have biased our results. We also excluded patients who were still in the diagnostic work-up stage and this might have influenced our results as it is known that patients dropout at this stage. As the PCQ-Infertility was validated in patients who were already undergoing treatment, we decided to focus on this patient group only. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study provide a better insight into those factors influencing dropout from the perspective of factors in the clinic itself. Although most clinic factors were not related to dropout, clinic factors might be of use when predicting dropout for specific patient groups, such as patients receiving ART and non-ART. Future research should involve an exploration of more specific predictors of dropout at the patient, treatment and clinic levels. STUDY FUNDING/COMPETING INTERESTS: This work was supported by Merck Serono, the Netherlands. No competing interests declared.

Unexplained infertility: overall ongoing pregnancy rate and mode of conception.

BACKGROUND: Unexplained infertility is one of the most common diagnoses in fertility care. The aim of this study was to evaluate the outcome of current fertility management in unexplained infertility. METHODS: In an observational, longitudinal, multicentre cohort study, 437 couples were diagnosed with unexplained infertility and were available for analysis. They were treated according to their prognosis using standing national treatment protocols: (i) expectant management-IUI-IVF (main treatment route), (ii) IUI-IVF and (iii) directly IVF. Primary outcome measures were: ongoing pregnancy rate, patient flow over the strategies, numbers of protocol violation and drop out rates. A secondary outcome measure was the prediction of ongoing pregnancy and mode of conception. RESULTS: Of all couples 81.5% (356/437) achieved an ongoing pregnancy and 73.9% (263/356) of the pregnancies were conceived spontaneously. There were 408 couples (93.4%) in strategy-1, 21 (5.0%) in strategy-2 and 8 (1.8%) in strategy-3. In total, 33 (7.6%) couples entered the wrong strategy. There were 104 couples (23.8%) who discontinued fertility treatment prematurely: 26 on doctor's advice (with 4 still becoming pregnant) and 78 on their own initiative (with 33 still achieving a pregnancy). Predictors for overall pregnancy chance and mode of conception were duration of infertility, female age and obstetrical history. CONCLUSIONS: Overall success rate in couples with unexplained infertility is high. Most pregnancies are conceived spontaneously. We recommend that if the pregnancy prognosis is good, expectant management should be suggested. The prognosis criteria for treatment with IUI or IVF needs to be investigated in randomized controlled trials.

Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins.

BACKGROUND: Long-term effects of laparoscopic electrocautery of the ovaries are unknown. To study the long-term effects of laparoscopic electrocautery of the ovaries and gonadotrophins, we followed women with clomiphene-resistant polycystic ovary syndrome (PCOS) randomly allocated to one of these treatments until 8-12 years after their initial treatment. METHODS: Between February 1998 and October 2001 168 women with clomiphene citrate-resistant PCOS were included in a randomized controlled trial comparing an electrocautery strategy to a strategy starting with rFSH. In 2009 these women were contacted about their reproductive outcome and menstrual cycle regularity. Analysis was by intention-to-treat. We compared time to conception resulting in live birth, subsequent pregnancies, ectopic and multiple pregnancies, menopause, as well as minimal and maximal menstrual cycle length. RESULTS: After 8-12 years, the cumulative proportion of women with a first child was 86% in women who had been allocated to electrocautery versus 81% in women who had been allocated to immediate rFSH [relative ratio (RR): 1.1; 95% confidence interval (CI): 0.92-1.2]. Treatment with electrocautery resulted in a significantly lower need for stimulated cycles to reach a live birth; 53% after electrocautery versus 76% after rFSH (RR: 0.69; 95% CI: 0.55-0.88).The cumulative proportion of women with a second child was 61% after electrocautery versus 46% after immediate rFSH (RR: 1.4; 95% CI: 1.00-1.9). Overall, there were 7 twins out of 134 deliveries (5%) after electrocautery versus 10 twins out of 124 deliveries (8%) in the rFSH group (RR: 0.65; 95% CI: 0.25-1.6). Fifty-four per cent of the women allocated to electrocautery had a regular menstrual cycle 8-12 years after randomization versus 36% in those allocated to rFSH (RR: 1.5; 95% CI: 0.87-2.6). CONCLUSION: In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries is as effective as ovulation induction with FSH treatment in terms of live births, but reduces the need for ovulation induction or ART in a significantly higher proportion of women and increases the chance for a second child. Clinicians may use these data when informing clomiphene-resistant anovulatory women about treatment options.

Severity of oligo-asteno-teratozoospermia no longer determines overall success rate in male subfertility.

In this longitudinal multicentre cohort study, the overall ongoing pregnancy rate after current evidence-based management in male subfertility was studied. All subfertile couples who visited the fertility clinic for the first time between 2002 and 2006, and had male subfertility as a single diagnosis (n = 762 of 2476 couples), were included in this study. Couples were grouped by the severity of male factor. Group I (n = 541) had a total motile sperm count (TMSC) 1-20 × 10(6). Group II (n = 161) had a TMSC <1 × 10(6). Group III (n = 60) had azoospermia. The overall ongoing pregnancy rate was 65.5% (500/762). The overall ongoing pregnancy rates in group I (69.3%) and group II (61.5%) were comparable (p = 0.06). However, group I and group II conceived significantly more frequently than group III (43.3%) (group I vs. group III p < 0.001 and group II vs. group III p = 0.02, respectively). Moreover, the spontaneous ongoing pregnancy rate in group I was 35.3%, in group II 22.4% and in group III, 1.7% (group I vs. group II p = 0.002; group I vs. group III p < 0.001; group II vs. group III p < 0.001). Thus, despite a significant difference in spontaneous ongoing pregnancy rates, except for azoospermia, the overall ongoing pregnancy rates, regardless of the severity of the male factor, were comparable. Couples with poorer sperm parameters, however, have to undergo more invasive treatment to reach the same goal.

Is the fertility treatment itself a risk factor for early pregnancy loss?

This longitudinal multicentre cohort study aimed to identify the role of the conception mode in infertile couples with an early pregnancy loss (EPL). All couples referred to the fertility clinic for the first time in the period 2002-2006 because of infertility were followed up to their first clinical pregnancy (n=1809). EPL was the outcome of 286 (15.8%) pregnancies. EPL rates for the different conception modes were as follows: spontaneous 14.5% (125/864), ovulation induction 15.8% (42/266), intrauterine insemination 25.0% (5/20), intrauterine insemination combined with ovarian stimulation 18.2% (37/203), IVF 16.3% (31/190), intracytoplasmic sperm injection (ICSI) 14.9% (30/202) and frozen embryo transfer (FET) 26.2% (16/61). After adjusting for female age, male age, hospital, obstetric history, female smoking habit, male alcohol use, menstrual cycle type and infertility diagnosis, the EPL rate after FET was significantly increased (odds ratio 2.2, 95% CI 1.14-4.19) compared with spontaneous conception. Embryo quality was comparable in fresh and frozen embryos. Other fertility treatments showed no increased miscarriage rate. Therefore, it is concluded that even after adjustment for confounding factors conception through FET remained an independent risk factor for EPL. Other modes of conception were not related with EPL.

A concise infertility work-up results in fewer pregnancies.

STUDY QUESTION: Is pregnancy success rate after a concise infertility work-up the same as pregnancy success rate after the traditional extensive infertility work-up? SUMMARY ANSWER: The ongoing pregnancy rate within a follow-up of 1 year after a concise infertility work-up is significantly lower than the pregnancy success rate after the traditional and extensive infertility work-up. WHAT IS KNOWN ALREADY: Based on cost-effectiveness studies, which have mainly focused on diagnosis, infertility work-up has become less comprehensive. Many centres have even adopted a one-stop approach to their infertility work-up. STUDY DESIGN SIZE DURATION: We performed a historically controlled cohort study. In 2012 and 2013 all new infertile couples (n = 795) underwent an extensive infertility work-up (group A). In 2014 and 2015, all new infertile couples (n = 752) underwent a concise infertility work-up (group B). The follow-up period was 1 year for both groups. Complete follow-up was available for 99.0% of couples in group A and 97.5% in group B. PARTICIPANTS/MATERIALS SETTING METHODS: The extensive infertility work-up consisted of history taking, a gynaecological ultrasound scan, semen analysis, ultrasonographic cycle monitoring, a timed postcoital test, a timed progesterone and chlamydia antibody titre. A hysterosalpingography (HSG) was advised routinely. The concise infertility work-up was mainly based on history taking, a gynaecological ultrasound scan and semen analysis. A HSG was only performed if tubal pathology was suspected or before the start of IUI. Laparoscopy and hormonal tests were only performed if indicated. Couples were treated according to the diagnosis with either expectant management (if the Hunault prognostic score was >30%), ovulation induction (in case of ovulation disorders), IUI in natural cycles (in case of cervical factor), IUI in stimulated cycles (if the Hunault prognostic score was <30%) or IVF/ICSI (in case of tubal factor, advanced female age, severe male factor and if other treatments remained unsuccessful). The primary outcomes were time to pregnancy and the ongoing pregnancy rates in both groups. The secondary outcomes were the number of investigations, the distribution of diagnoses made, the first treatment (started) after infertility work-up and the mode of conception. MAIN RESULTS AND THE ROLE OF CHANCE: The descriptive data, such as age, duration of infertility, type of infertility and lifestyle habits, in both groups were comparable. In group A, more than twice the number of infertility investigations were performed, compared to group B. An HSG was made less frequently in group B (33% versus 42%) and at a later stage. A Kaplan-Meier curve shows a shorter time to pregnancy in group A. Also, a significantly higher overall ongoing pregnancy rate within a follow-up of 1 year was found in group A (58.7% versus 46.8%, respectively, P < 0.001). In group A, more couples conceived during the infertility work-up (14.7% versus 6.5%, respectively, P < 0.05). The diagnosis cervical infertility could only be made in group A (9.3%). The diagnosis unexplained infertility differed between groups, at 23.5% in group A and 32.2% in group B (P < 0.001). LIMITATIONS REASONS FOR CAUTION: This was a historically controlled cohort study; introduction of bias cannot be ruled out. The follow-up rate was similar in the two groups and therefore could not explain the differences in pregnancy rate. WIDER IMPLICATIONS OF THE FINDINGS: Re-introduction of an extensive infertility work-up should be considered as it may lead to higher ongoing pregnancy rates within a year. The therapeutic effects of HSG and timing of intercourse may improve the fertility chance. This finding should be verified in a randomized controlled trial. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained for this study. No conflicts of interest were declared. TRIAL REGISTRATION NUMBER: N/A.

The relative contribution of IVF to the total ongoing pregnancy rate in a subfertile cohort.

BACKGROUND: Although in vitro fertilization (IVF) was introduced more than 30 years ago, its exact role in the spectrum of fertility treatments has never been studied in an unselected population. The aim of this study was to visualize the contribution of IVF to the ongoing pregnancy rates in a cohort of newly referred subfertile couples. MATERIALS: All new subfertile couples (n = 1391) that were referred to our fertility clinic by their general practitioner between January 2002 and December 2006 were included. Fertility care was provided according to the national Dutch fertility guidelines. Data on diagnosis, treatment, mode of conception and pregnancy outcome were documented. If follow-up data were missing, couples were contacted. Cumulative pregnancy curves were constructed for the whole cohort and per diagnostic group. RESULTS: As per December 2008 the overall ongoing pregnancy rate was 72.0% (n = 1001). Almost half of the pregnancies were conceived spontaneously (45.6%), 19.2% after ovulation induction (OI), 14.0% after intrauterine insemination (IUI) and 21.2% after IVF. A quarter (n = 349) of couples received IVF treatment, which was successful in 60% of cases. IVF had the largest contribution to ongoing pregnancies in patients with 'tubal factor', 'endometriosis' and 'male factor' (45, 45 and 37%, respectively) while in couples with 'unexplained subfertility' and 'ovulation disorders' the contribution to ongoing pregnancies of IVF was limited (13 and 4.5%, respectively). CONCLUSIONS: In a cohort of subfertile couples, most pregnancies were conceived spontaneously. The contribution of IVF to ongoing pregnancy rates was comparable to those of OI and IUI. Compared with the pre-IVF era, couples with 'endometriosis', 'tubal factor' and 'male subfertility' have benefited most from its introduction.

When and why do subfertile couples discontinue their fertility care? A longitudinal cohort study in a secondary care subfertility population.

BACKGROUND: A substantial number of subfertile couples discontinues fertility care before achieving pregnancy. Most studies on dropouts are related to IVF. The aim here is to examine dropout rates at all stages of fertility care. METHODS: We analysed a consecutive cohort of 1391 couples, referred to our secondary care hospital between January 2002 and December 2006. Discontinuation rates were studied at six stages. Stage I: immediately after first visit, Stage II: during diagnostic workup, Stage III: after finishing diagnostic workup but before treatment, Stage IV: during or after non-IVF treatment, Stage V: during IVF, Stage VI: after at least 3 cycles of IVF. Reasons to discontinue and spontaneous pregnancy rates after discontinuation were secondary outcomes. RESULTS: In our cohort 319 couples dropped out of fertility care, 76.8%, [95% confidence interval (CI): 72.2-81.4] on their own initiative and 23.2% (95% CI: 18.6-27.8) on doctor's advice. Percentage (95% CI) of couples discontinuing per stage were: Stage I 6.0% (3.4-8.6), Stage II 3.4% (1.5-5.5), Stage III 35.7% (30.5-41.0), Stage IV 23.5% (18.9-28.2), Stage V 17.9% (13.7-22.1) and Stage VI 13.5% (9.7-17.2). Main reasons for dropout (%, 95% CI) were 'emotional distress' (22.3%, 17.7-26.8), 'poor prognosis' (18.8%, 14.5-23.1) and 'reject treatment' (17.2%, 13.1-21.4). The spontaneous ongoing pregnancy rate after discontinuation was 10% (6.7-13.3). CONCLUSION: About half of the couples stopped before any fertility treatment was started and one-third stopped after at least one IVF cycle. The main reasons for withdrawal were emotional distress and poor prognosis. This insight may help to improve quality of patient care by making care more responsive to the needs and expectations of subfertile couples.

Placental histopathology after Coxiella burnetii infection during pregnancy.

Symptomatic and asymptomatic Coxiella burnetii infection during pregnancy have been associated with obstetric complications. We described placental histopathology and clinical outcome of five cases with asymptomatic C. burnetii infection during pregnancy and compared these cases with four symptomatic cases from the literature. In contrast with the symptomatic cases, we did not observe necrosis or active inflammation in the placentas of the asymptomatic women. Obstetrical outcome was more favourable in the asymptomatic cases than in the symptomatic cases. Asymptomatic and symptomatic C. burnetii infection during pregnancy are different entities with respect to placental histopathology and the risk of obstetric complications.

The length of the fertile window is associated with the chance of spontaneously conceiving an ongoing pregnancy in subfertile couples.

BACKGROUND: The period in each menstrual cycle during which sexual intercourse can result in conception is called the "fertile window". Although the fertile window closes on the day of ovulation, little is known about the moment it opens. We defined the first day of normal sperm-mucus interaction as the opening of the fertile window. We hypothesized that length of the fertile window varies between couples and that the number of days the fertile window is "open" is related to the time to spontaneous conception. METHODS Serial post-coital tests and sperm-mucus penetration tests were performed to detect the first normal sperm-mucus interaction day. Ovulation was confirmed by serial ultrasound. Using Cox' regression analysis, we determined whether the fertile window length was associated with time to ongoing pregnancy. This association was expressed in fecundability ratios (FR). RESULTS The fertile window length was determined in 410 subfertile couples. The fertile window length varied among couples from <1 to >5 days. The FR increased with increasing fertile window length and varied between 0.11 (95% CI: 0.03-0.45) for a fertile window of 1 day, to 2.4 (95% CI: 1.1-5.2) for a fertile window of 5 days or more. CONCLUSIONS The longer the fertile window in subfertile couples, the higher is the probability of spontaneously conceiving an ongoing pregnancy.

A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility.

BACKGROUND: Controlled ovarian hyperstimulation with intrauterine insemination (IUI) is a widely accepted treatment for unexplained and male subfertility. No consensus exists about the drug of first choice to be used as hyperstimulation. This randomized multicentre trial using a parallel design compares the efficacy of clomiphene citrate (CC) with that of recombinant FSH (rFSH). METHODS: Couples with primary unexplained or male subfertility were randomized to receive CC or rFSH for ovarian hyperstimulation. The treatment was continued for up to four cycles unless pregnancy occurred. Cycles with more than three follicles were cancelled. Cumulative pregnancy rates and live birth rates were primary outcomes. Cancellation during treatment and multiple birth rates are secondary outcomes. Results were analysed following the intention-to-treat principle. RESULTS: Seventy couples with male subfertility and 68 couples with unexplained subfertility were included. Seventy-one women received CC, and 67 received rFSH. Twenty-seven pregnancies were observed in the CC group (38%) and 23 in the rFSH group (34.3%) relative risk (RR) 1.11 [95% confidence interval (95% CI) 0.71-1.73]. The live birth rate was 28.2% (20/71) and 26.9% (18/67) for CC and rFSH, respectively, RR 1.05 (95% CI 0.61-1.80). Overall, the live birth rates per cycle were 10% for CC-stimulated and 8.7% for rFSH stimulated cycles. The total multiple pregnancy rate was 6.0%. Thirty-five cycles (8.6%) were cancelled because of four or more follicles (CC, n = 17; rFSH, n = 18). CONCLUSIONS: In couples with primary unexplained or male subfertility participating in an IUI program, ovarian hyperstimulation can be achieved by CC or rFSH. No significant difference in live birth rates between CC and rFSH was observed. Being less expensive, CC seems the more cost-effective drug and therefore, can be offered as drug of first choice.