C.J.C.M. Hamilton

Prediction of successful embryo implantation by measuring interleukin-1-alpha and immunosuppressive factor(s) in preimplantation embryo culture fluid*

To find a better predictor of pregnancy after in vitro fertilization (IVF), supernatant fluids from embryo culture media were analyzed after 24 hours and 48 hours for the presence of interleukin-1-alpha (IL-1), interleukin-2, and the percent of immunosuppression. The measurements were performed on 108 consecutive IVF cycles between June 1989 and October 1989. The IL-1 level +/- SD in the 24-hour aliquots of the supernatant of embryo culture fluid was 66.2 +/- 10.2 pg/mL in all viable pregnancy cycles and 35.4 +/- 9.01 pg/mL in unsuccessful cycles. The percent of immunosuppression after 24 hours was 22.06% +/- 4.5% in viable pregnancy cycles and 7.3 +/- 5.5% in unsuccessful cycles. The percent of immunosuppression 48 hours after ovum pick-up was generally decreased in all embryo culture fluid, showing 17.5% +/- 4.4% in viable pregnancy cycles and 3.8% +/- 3.6% in unsuccessful cycles. Interleukin-1 levels in the 48-hour aliquots were moderately decreased, being 39.0 +/- 6.3 pg/mL in viable pregnancy cycles and 34.3 +/- 4.7 pg/mL in the unsuccessful cycles. In 24 hours, embryo culture aliquots IL-1 level greater than 60 pg/mL was seen in 17 of 21 (80.9%) pregnancy cycles, and the combined data of IL-1 level greater than 60 pg/mL and/or greater than 20 percent of immunosuppression predicted 21 of 21 (100%) pregnancy cycles.

Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome

A prospective longitudinal and standardized study is presented, dealing with ultrasonographic and hormonal characteristics of the luteinized unruptured follicle (LUF) syndrome. Among 600 cycles monitored in 270 infertility patients, 40 cycles in 27 patients showed no evidence of follicle rupture, in spite of signs of luteinization, as reflected by basal body temperature recordings and progesterone determinations. In this study, 20 LUF cycles in 20 infertile patients were compared with 45 ovulatory cycles in 45 control women. During the follicular phase, no substantial difference in follicle growth was found, but after the luteinizing hormone peak, LUF follicles, instead of rupturing, showed a typical accelerated growth pattern. Both mean luteinizing hormone peak levels and midluteal progesterone levels were significantly lower in LUF cycles than in the control cycles. However, the duration of the luteal phase was not affected. Both central and local factors can be held responsible for the lack of follicle rupture. Ultrasound offers new possibilities as a noninvasive method in diagnosing the LUF syndrome.

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 doctors 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.

The impact of the woman's age on the success of standard and donor in vitro fertilization

OBJECTIVE To study the effect of the age of the woman who provides the oocytes or who receives the embryos on results of IVF-ET. DESIGN Historical cohort study. Multivariate regression analysis was used to study the age effect continuously and after adjustment for confounding. SETTING Patients of the University of Southern California, Los Angeles, California. PATIENT(S) Couples who underwent standard (n = 277) or donor IVF-ET (n = 294) between January 1991 and July 1995. INTERVENTION(S) One cycle of standard or donor IVF-ET. MAIN OUTCOME MEASURE(S) Successive IVF outcomes from number of oocytes to ongoing pregnancy and several measures of pregnancy loss. RESULT(S) The number of oocytes decreased with aging of the oocyte provider. More women who received oocytes from donors aged 20 to 23 years had at least one good embryo transferred than women who received oocytes from older donors. The age of the woman who received the embryos had no effect on IVF outcomes. In women > 40 years who underwent standard IVF, the probability of pregnancy decreased. No such relationships were observed for donor IVF, but all the oocyte donors were younger. CONCLUSION(S) An age effect for ongoing pregnancy was only found in women > 40 years who underwent standard IVF independent of the lower number of oocytes and suggests decreasing oocyte quality.

A more realistic approach to the cumulative pregnancy rate after in-vitro fertilization

As most studies overestimate the cumulative pregnancy rate, a method is proposed to estimate a more realistic cumulative pregnancy rate by taking into account the reasons for an early cessation of treatment with in-vitro fertilization (IVF). Three methods for calculating cumulative pregnancy rates were compared. The first method assumed that those who stopped treatment had no chance at all of pregnancy. The second method, the one used most often, assumed the same probability of pregnancy for those who stopped as for those who continued. The third method assumed that only those who stopped treatment, because of a medical indication, had no chance at all of pregnancy and that the others who stopped had the same probability of pregnancy as those who continued treatment. Data were used from 616 women treated at the University Hospital Nijmegen, Nijmegen, The Netherlands. The cumulative pregnancy rates after five initiated IVF cycles for the three calculation methods were in the ranges 37-51% for the positive pregnancy test result, 33-55% for a clinical pregnancy and 30-56% for an ongoing pregnancy. As expected, the first method underestimated the cumulative pregnancy rate and the second overestimated it. The third method produced the most realistic cumulative pregnancy rates.

Longitudinal ultrasonographic study of the ovarian suppressive activity of a low-dose triphasic oral contraceptive during correct and incorrect pill intake

A longitudinal study was conducted to evaluate the ability of a low-dose triphasic oral contraceptive to suppress ovulation as documented by frequent ultrasonographic scanning and progesterone determinations, even in the event of a missed pill. The extent of follicular growth and maturation, the incidence of escape ovulation, and the effect of correct and incorrect pill intake were assessed in 30 evaluable women during two consecutive spontaneous menstrual cycles. After the first cycle, 11 of 30 women (36.6%) had follicle-like structures of at least 10 mm in diameter. Ten of 11 structures gradually disappeared during the second cycle, with one persistent structure remaining through the second cycle. Seven of 30 women (23%) developed follicle-like structures during the second cycle. Of these, one woman had a probable ovulation, and another had an elevated progesterone level without follicle rupture, suggesting the luteinized unruptured follicle syndrome. Both of these women missed a pill on day 1 of the second cycle. In all cases cervical scores indicating hostility were noted. Thus, although suppression of ovarian activity may have been incomplete when oral contraceptives were incorrectly taken, secondary mechanisms of contraception remained operant. When they were correctly taken, low-dose triphasic oral contraception consistently prevented ovulation.

Controlled comparison of interceed and amniotic membrane graft in the prevention of postoperative adhesions in the rabbit uterine horn model.

OBJECTIVE To evaluate the effects of Interceed TC7 (Johnson & Johnson Medical, New Brunswick, NJ) and gamma-irradiated human amniotic membrane graft in prevention of postoperative adhesions in the rabbit uterine horn model. SETTING A conventional animal laboratory. SUBJECTS Virgin, female New Zealand white rabbits. INTERVENTIONS Both uterine horns were subjected to clean transverse cuts 1 cm apart at the antimesenteric border. The left uterine horn was left uncovered in each case to act as a control. The right uterine horn was randomly covered with either Interceed TC7 or human amniotic membrane. OUTCOME MEASURES Adhesion score was evaluated 4 weeks after the initial surgery. Samples of each uterine horn were collected for histopathological studies, and subserosal inflammatory score. RESULTS Interceed resulted in higher adhesion scores and subserosal inflammation score than the control side (P = 0.03 and 0.05, respectively). A similar difference was found for amniotic membrane when compared with the uncovered control side (P = < 0.01 and 0.01, respectively). CONCLUSION Interceed TC7 failed to have the preventive effect on adhesion formation it is claimed to possess. Amniotic membrane performed poorly too. Therefore, gentle tissue handling, irrigation and good surgical skills remain the most important prerequisite for adhesion prevention.

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.

Intramural pregnancy after in vitro fertilization and embryo transfer

A case of intramural but not interstitial pregnancy, established after IVF/ET, is described. The etiologic, diagnostic, and therapeutic aspects of this clinical dilemma are discussed.

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.