Tarek A. Gelbaya

Circulating basal anti-Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization.

OBJECTIVE To evaluate the clinical value of basal anti-Müllerian hormone (AMH) measurements compared with other available determinants, apart from chronologic age, in the prediction of ovarian response to gonadotrophin stimulation. DESIGN Prospective cohort study. SETTING Tertiary referral center for reproductive medicine and an IVF unit. PATIENT(S) Women undergoing their first cycle of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). MATERIALS AND METHODS Basal levels of FSH and AMH as well as antral follicle count (AFC) were measured in 165 subjects. All patients were followed prospectively and their cycle outcomes recorded. MAIN OUTCOME MEASURE(S) Predictive value of FSH, AMH, and AFC for extremes of ovarian response to stimulation. RESULT(S) Out of the 165 women, 134 were defined as normal responders, 15 as poor responders, and 16 as high responders. Subjects in the poor response group were significantly older then those in the other two groups. Anti-Müllerian hormone levels and AFC were markedly raised in the high responders and decreased in the poor responders. Compared with FSH and AFC, AMH performed better in the prediction of excessive response to ovarian stimulation-AMH area under receiver operating characteristic curve (ROC(AUC)) 0.81, FSH ROC(AUC) 0.66, AFC ROC(AUC) 0.69. For poor response, AMH (ROC(AUC) 0.88) was a significantly better predictor than FSH (ROC(AUC) 0.63) but not AFC (ROC(AUC) 0.81). AMH prediction of ovarian response was independent of age and PCOS. Anti-Müllerian hormone cutoffs of >3.75 ng/mL and <1.0 ng/mL would have modest sensitivity and specificity in predicting the extremes of response. CONCLUSION(S) Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC, and has the potential to be incorporated in to work-up protocols to predict patients ovarian response to treatment and to individualize strategies aiming at reducing the cancellation rate and the iatrogenic complications of COH.

The effect of surgical treatment for endometrioma on in vitro fertilization outcomes: a systematic review and meta-analysis

OBJECTIVE To investigate the effect of surgical treatment of endometrioma on pregnancy rate and ovarian response to gonadotrophin stimulation in women undergoing IVF. DESIGN A systematic review and meta-analysis. SETTING Tertiary referral center for reproductive medicine. PATIENT(S) Subfertile women with endometrioma undergoing IVF. INTERVENTION(S) Surgical removal of endometrioma or expectant management. MAIN OUTCOME MEASURE(S) Clinical pregnancy rate and ovarian response to gonadotrophins (number of gonadotrophin ampoules, peak E(2) levels, number of oocytes retrieved, and number of embryos available for transfer). RESULT(S) A search of three electronic databases for articles published between January 1985 and November 2007 yielded 20 eligible studies. Meta-analysis was conducted for five studies that compared surgery vs. no treatment of endometrioma. There was no significant difference in clinical pregnancy rate between the treated and the untreated groups. Similarly, no significant difference was found between the two groups with regard to the outcome measures used to assess the response to controlled ovarian hyperstimulation with gonadotrophins. CONCLUSION(S) Collectively the available data in the literature show that surgical management of endometriomas has no significant effect on IVF pregnancy rates and ovarian response to stimulation compared with no treatment. Randomized controlled trials are needed before producing best-practice recommendations on this topic.

The risk of monozygotic twins after assisted reproductive technology: a systematic review and meta-analysis

BACKGROUND It is estimated that there is at least a 2-fold rise in the incidence of monozygotic twinning after assisted reproductive technology compared with natural conception. This can result in adverse pregnancy outcomes. METHODS We searched MEDLINE, EMBASE and SCISEARCH for studies that estimated the risk of monozygotic twinning and its association with any particular assisted reproductive technique. Monozygotic twinning was defined by ultrasound or Weinberg criteria. A meta-analysis of the proportion of monozygotic twins was performed using both fixed and random effects models. RESULTS The search revealed 37 publications reporting on the incidence of monozygotic twins after assisted reproductive techniques. Twenty-seven studies met the inclusion criteria and were included in the meta-analysis. The summary incidence of monozygotic twins after assisted conception was 0.9% (0.8-0.9%). The incidence of monozygotic twins in natural conception is 0.4%. Blastocyst transfer and intracytoplasmic sperm injection are associated with 4.25 and 2.25 times higher risk of monozygotic twins. CONCLUSIONS The risk of monozygotic twins in assisted conception is 2.25 times higher than the natural conceptions. Larger studies reporting on monozygotic twinning following single-embryo transfer or after post-natal confirmation of zygosity with DNA analysis are warranted before definitive conclusions can be drawn and guidelines produced. In order to provide adequate pre-conceptional counselling, it is important to monitor the incidence of monozygotic twins in both natural and assisted conceptions. We suggest building a national multiple pregnancy database based on accurate diagnosis of zygosity.

The likelihood of live birth and multiple birth after single versus double embryo transfer at the cleavage stage: a systematic review and meta-analysis

OBJECTIVE To determine whether a policy of elective single-embryo transfer (e-SET) lowers the multiple birth rate without compromising the live birth rate. DESIGN Systematic review and meta-analysis. SETTING Tertiary referral center for reproductive medicine and IVF unit. PATIENT(S) None. INTERVENTION(S) Searches of the Cochrane Controlled Trials Register, Meta-register for Randomized Controlled Trials (RCTs), EMBASE, MEDLINE, and SCISEARCH with no limitation on language and publication year, 1974 to 2008. SELECTION CRITERIA randomized, controlled trials comparing e-SET with double-embryo transfer (DET) for live birth and multiple birth rates after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). Nonrandomized trials and studies that included only patients who had blastocyst transfer were excluded. MAIN OUTCOME MEASURE(S) The likelihood of live birth per patient and multiple birth per total number of live births. Other outcomes included implantation rate, pregnancy rate, miscarriage and ectopic pregnancy rates, clinical pregnancy rate, ongoing pregnancy rate per patient, and preterm delivery rate per live birth. RESULT(S) Six trials (n=1354 patients) were included in the meta-analysis. Compared with DET, the e-SET policy was associated with a statistically significant reduction in the probability of live birth (RR 0.62; 95% CI, 0.53-0.72) and multiple birth (RR 0.06; 95% CI, 0.02-0.18). CONCLUSION(S) Elective-SET of embryos at the cleavage stage reduces the likelihood of live birth by 38% and multiple birth by 94%. Evidence from randomized, controlled trials suggests that increasing the number of e-SET attempts (fresh and/or frozen) results in a cumulative live birth rate similar to that of DET. Offering subfertile women three cycles of IVF will have a major impact on the uptake of an e-SET policy.

The use of anti-Müllerian hormone and antral follicle count to predict the potential of oocytes and embryos

OBJECTIVE To investigate whether anti-Müllerian hormone (AMH) is better than antral follicle count (AFC) in predicting oocyte yield and embryo quality after controlled ovarian hyperstimulation for in vitro fertilization (IVF). STUDY DESIGN This is a prospective observational study involving 162 women (<40 years old) undergoing their first IVF cycle at an IVF unit within a university hospital. AMH and AFC measurements were made on day 3 of the cycle within 3 months of starting ovarian stimulation. A standard long down-regulation protocol using gonadotrophin releasing hormone agonist and recombinant follicle stimulating hormone was used. A maximum of two embryos were transferred on day 2 or 3 following oocyte retrieval. The primary outcome was the number of good quality embryos available for transfer and freezing. Embryos were graded according to the number of blastomeres, the difference in blastomere size and the degree of fragmentation, into grades 1-4. Secondary outcomes included the number of oocytes retrieved and fertilized and the live birth rate. Correlation between different parameters was calculated using Spearmans correlation coefficient. Receiver operating characteristic (ROC) curves were generated for AMH and AFC to compare ability of parameters to predict top quality or frozen embryos and the occurrence of a live birth. RESULTS Of the 137 women who had fresh embryo transfer, 52 became pregnant (32.1% pregnancy rate per cycle started) and 38 had a live birth (23.5% live birth rate per cycle started). Both AMH and AFC had highly significant correlations with the number of oocytes retrieved and the number of oocytes fertilized (P<0.001). The two markers were also significantly associated with the number of top quality embryos available for transfer and the number of embryos frozen (P<0.01). With regard to live birth, AMH performed better than AFC (P<0.01 and P<0.05, respectively), but both markers were more valuable in predicting the absence rather than the occurrence of live birth (negative predictive value 84%). CONCLUSIONS AMH and AFC are comparable predictors of oocytes retrieved and of the number of good quality embryos available for transfer and freezing. Prediction of live birth may help clinicians selecting patients suitable for single embryo transfer.

The use of estradiol for luteal phase support in in vitro fertilization/intracytoplasmic sperm injection cycles: a systematic review and meta-analysis

OBJECTIVE To investigate the effect of luteal E(2) supplementation on the pregnancy rate of IVF/intracytoplasmic sperm injection (ICSI) cycles. DESIGN A systematic review and meta-analysis of all the randomized controlled trials (RCTs). SETTING Tertiary referral center for reproductive medicine and IVF. PATIENT(S) Women undergoing IVF or ICSI using the GnRH agonist or GnRH antagonist protocol with hMG or FSH for controlled ovarian hyperstimulation. INTERVENTION(S) Progesterone (P4) alone or combined with estradiol valerate for luteal phase support. MAIN OUTCOME MEASURE(S) Pregnancy and clinical pregnancy rates per ET. RESULT(S) An electronic search was conducted targeting all reports published between January 1960 and March 2007. Ten RCTs met the criteria for inclusion in the meta-analysis. There were no statistically significant differences with regard to the main outcome measures, ongoing pregnancy rate per ET, or implantation rate between the group of women who had combined E(2) and P4 therapy and those who had P4 supplementation alone. CONCLUSION(S) The addition of E(2) to P4 for luteal phase support in IVF/ICSI cycles has no beneficial effect on pregnancy rates. The data in the literature are, however, limited and heterogeneous, precluding the extraction of clear and definite conclusions. A large multicenter, properly designed RCT is needed to further clarify the role of luteal E(2) supplementation in IVF.

The optimal length of 'coasting protocol' in women at risk of ovarian hyperstimulation syndrome undergoing in vitro fertilization

Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially life-threatening complication following ovarian stimulation for in vitro fertilization (IVF). Coasting is the practice whereby the gonadotrophins are withheld and the administration of human chorionic gonadotrophin (hCG) is delayed until serum oestradiol (E2) has decreased to what is considered to be a safe level, to prevent the onset of OHSS. This study aimed to assess the length of coasting on the reproductive outcome in women at risk of developing OHSS. Coasting was undertaken when the serum E2 concentrations were ≥17000 pmol/L but <21000 pmol/L. Daily E2 measurements were performed and hCG was administered when hormone levels decreased to <17000 pmol/L. Eighty-one women who had their stimulation cycles coasted were grouped according to the number of coasting days. Severe OHSS occurred in one case, which represented 1.2% of patients who underwent coasting because of an increased risk of developing the syndrome. No difference was found between cycles coasted for 1 – 3 days and cycles coasted for ≥4 days in terms of oocyte maturity, fertilization and embryo cleavage rates. Women in whom coasting lasted for ≥4 days had significantly fewer oocytes retrieved (P < 0.05) and decreased implantation rate (P < 0.05) compared to those coasted for 1 – 3 days. Pregnancy rate/embryo transfer and live birth rate did not differ between groups. In conclusion, coasting appears to decrease the risk of OHSS without compromising the IVF cycle pregnancy outcome. Prolonged coasting is, however, associated with reduced implantation rates, perhaps due to the deleterious effects on the endometrium rather than the oocytes.

Definition and epidemiology of unexplained infertility.

The diagnosis of unexplained infertility can be made only after excluding common causes of infertility using standard fertility investigations, which include semen analysis, assessment of ovulation, and tubal patency test. These tests have been selected as they have definitive correlation with pregnancy. It is estimated that a standard fertility evaluation will fail to identify an abnormality in approximately 15% to 30% of infertile couples. The reported incidence of such unexplained infertility varies according to the age and selection criteria in the study population. We conducted a review of the literature via MEDLINE. Articles were limited to English-language, human studies published between 1950 and 2013. Since first coined more than 50 years ago, the term unexplained infertility has been a subject of debate. Although additional investigations are reported to explain or define other causes of infertility, these have high false-positive results and therefore cannot be recommended for routine clinical practice. Couples with unexplained infertility might be reassured that even after 12 months of unsuccessful attempts, 50% will conceive in the following 12 months and another 12% in the year after. Target Audience Obstetricians and gynecologists, family Physicians Learning Objectives After completing this CME activity, physicians should be better able to identify the epidemiology of unexplained infertility and standard investigations for infertile couples and to consider other possible causes of infertility before making a diagnosis of unexplained infertility.

Optimal dose of HCG for final oocyte maturation in IVF cycles: absence of evidence?

There is an ongoing debate over the optimal dose of urinary HCG (u-HCG) that can trigger final oocyte maturation, leading to higher IVF success rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS). A systematic review was conducted of all studies that compared the effect of at least two doses of u-HCG for final oocyte maturation on IVF outcomes and on the incidence of OHSS. The primary outcome was the live birth rate, and the secondary end-points were the number of oocytes retrieved, fertilization, implantation and pregnancy rates, and the incidence of OHSS. Only two amongst the six included studies were randomized controlled trials (RCT). Meta-analytic pool was not feasible due to insufficient number of studies assessing the same outcome and significant heterogeneity. The majority of studies concluded that the clinical outcomes were similar between women receiving 5000 or 10,000 IU of u-HCG. The incidence of OHSS was not reduced in the high-risk population even with lower dose of u-HCG. Until large scale RCT addressing the clinical effectiveness and the adverse outcomes related to various doses of u-HCG are conducted, the dose of u-HCG for final oocyte maturation for women referred for IVF needs to be individualized.