Factors associated with embryo splitting and clinical outcome of monozygotic twins in pregnancies after IVF and ICSI.

STUDY QUESTION: What factors are associated with monozygotic twins (MZT) after autologous IVF/ICSI with fresh and frozen/thawed single embryo transfer (SET) and what is the outcome of MZT? SUMMARY ANSWER: Factors associated with increased MZT were blastocyst transfer and elective single embryo transfer (eSET), with MZT showing a lower gestational age at birth and neonatal weight but higher perinatal mortality only after fresh transfer. WHAT IS KNOWN ALREADY: ART is associated with an increased incidence of MZT, which carries higher perinatal mortality. However, risk factors associated with MZT are still controversial. STUDY DESIGN SIZE DURATION: A population-based retrospective analysis of data extracted from ART cycles reported to the Latin American Registry of ART between January 2012 and December 2016 was used in order to study the frequency and outcome of MZT after SET. PARTICIPANTS/MATERIAL SETTING METHODS: In total, 2925 clinical pregnancies obtained after autologous IVF/ICSI with fresh SET were used to study biomedical factors possibly associated with MZT, such as maternal age, type of insemination, use of assisted hatching, stage of embryo development at transfer, elective or non-elective SET and preimplantation genetic testing. Another group of 3085 clinical pregnancies obtained after SET of frozen-thawed embryo transfer (FET) was also used to study the possible association between embryo freezing and MZT. Only pregnancies with complete follow-up until birth were included in this analysis. The diagnosis of MZT was established by transvaginal ultrasound performed at 6­8 weeks of amenorrhea. The rate of MZT for each potential risk factor was obtained and a multivariable logistic regression was performed in order to account for the above-mentioned factors. Pregnancies were followed until birth and the early neonatal period in order to assess the rate of miscarriage and stillbirths, gestational age at birth, neonatal weight and early neonatal mortality. MAIN RESULTS AND ROLE OF CHANCE: There were 76 MZT out of 2925 clinical pregnancies with fresh SET (2.6%) and 69 MZT out of 3085 clinical pregnancies after FET (2.2%) (odds ratio (OR) = 0.85, 95% CI 0.61­1.19). A statistically significantly increase in MZT rate was observed with blastocyst compared with cleavage stage ET (3.4 versus 2.0%, respectively; OR = 1.70, 95% CI 1.05­2.76). When confounding variables were considered, eSET was also significantly associated with an increase in the odds of MZT (OR = 1.74, 95% CI 1.04­2.92). Overall perinatal mortality was higher in MZT compared with singletons, but this rise was only significant after fresh ET. LIMITATIONS REASONS FOR CAUTION: Limitations of the current study result from the fact that MZT were diagnosed with ultrasound performed at 6­8 weeks of amenorrhea; therefore, spontaneous embryo reductions taking place earlier were missed. WIDER IMPLICATIONS OF THE FINDINGS: Reproductive health providers must inform their patients that blastocyst transfer and eSET of fresh embryos are associated with a statistically significantly increase in the odds of MZT and that perinatal mortality after fresh ET is significantly higher in MZT than in singletons. STUDY FUNDING/COMPETING INTERESTS: The Latin American Registry of ART receives direct funding from Ferring Pharmaceuticals, but no specific funding was received to undertake this study. None of the authors declare conflict of interest.

Multiple gestation as a marker of reproductive efficacy: learning from assisted reproductive technologies.

This study postulates that apart from the number of embryos transferred, women with multiple gestation represent a subgroup of highly fertile individuals, whose embryos implant with higher efficiency than women with single gestation. Furthermore, each embryo generated from these women has a higher chance of reaching full term. The objective of this study was to compare implantation rate with the outcome of pregnancy (up to week 20) in multiple gestations following assisted reproductive techniques. The study group comprised 162 women with multiple gestation after assisted reproduction, followed prospectively with at least three ultrasound examinations performed between weeks 5 and 20 after the last menstrual period. Control group A comprised 344 fertile women with spontaneous single pregnancy followed with transvaginal ultrasound. Control group B consisted of 317 infertile women conceiving with single gestation after assisted reproduction and followed prospectively as in the study group. Embryo implantation rate and spontaneous embryo/fetal reduction, either partial or total (abortion), were registered in each case. Overall implantation in women with multiple gestation was higher (54.6%) than in the corresponding controls (25.6%). Furthermore, spontaneous embryo/fetus reduction was similar in the study cases and in fertile women (12.6 and 10.8% respectively) and significantly smaller than in the control group B (20.8%). Women with high reproductive efficacy exposed to assisted reproductive techniques generate cohorts of good quality embryos, with a high chance of implantation and of reaching birth.

Results of assisted reproduction techniques in Latin America.

The fact that today it is possible to write a comprehensive report on assisted reproduction technologies in Latin America is the result of a serious and systematic effort, accomplished by more than 80 centres, from Mexico to Chile. Over the past 10 years, these centres representing the vast majority of assisted reproductive treatment cycles performed in Latin America, have agreed voluntarily to report their work to our regional registry using a pre-established format. Furthermore, during 1999 and part of 2000, all centres were visited by a team of biologists and clinicians, who evaluated for consistencies in the data reported. This activity also included an evaluation of personnel, facilities, etc. It can be proudly said that the data reported are a true reflection of the actual situation in our region.

Clinical management of functional ovarian cysts: a prospective and randomized study.

Most ovarian cysts in women of reproductive age are physiological (functional) and patients have been treated for years with oral contraceptives to obtain the resolution of these cysts. Expectant management has been suggested to have the same effectiveness as hormonal treatment but such suggestions come from studies including all kinds of cysts. The objective of the present study was to assess the resolution of functional ovarian cysts, observed after ovulation induction, with expectant management and hormonal treatment and also to determine the period of time necessary for the resolution of the cysts. For this purpose, 53 patients with ovarian cysts, observed by transvaginal ultrasound within the first 5 days of a cycle after ovulation induction, were randomized to have expectant management (group A) or to receive oral contraception (group B) for one cycle. If the cyst persisted, the patient was followed for another cycle, without any treatment. Within the 50 women who completed the trial, a complete resolution of the cysts was observed in 19/25 (76%) and 18/25 (72%) in groups A and B respectively. On the other hand, all the persistent cysts disappeared after a second cycle without any treatment. In conclusion, expectant management is as effective as oral contraceptives for the resolution of functional ovarian cysts induced by ovarian stimulation. However, studies with a larger number of cases are needed to increase the power of the results and to obtain a firm conclusion.

Prospective randomized trial to evaluate the efficacy of a vaginal ring releasing progesterone for IVF and oocyte donation.

A polysyloxane vaginal ring containing 1g of natural progesterone was developed as luteal supplementation for women treated with IVF-embryo transfer and for agonadal women participating in an oocyte donation programme. The ring provides continuous release of progesterone (10-20 nmol/l) for 90 days. The efficacy of this form of progesterone supplementation was evaluated in two multicentre prospective randomized trials. IVF-embryo transfer trial: After oocyte aspiration, 505 women were randomly allocated to progesterone supplementation with vaginal ring or i.m. progesterone (50 mg/day). The clinical pregnancy rate was 36.6% in both groups. Implantation rate was 15.9% in the vaginal ring and 16.0% in i.m. progesterone. Oocyte donation trial: After endometrial proliferation with micronized oestradiol, 153 women were allocated to progesterone replacement with a vaginal ring or i.m. progesterone (100 mg/day). Clinical pregnancy rate was 39.8 and 28.6% respectively. Implantation rate was significantly higher with the vaginal ring compared with i.m. progesterone (19.9 and 11.6% respectively, P = 0.006). The vaginal ring is a novel development which provides continuous release of progesterone for 90 days. In IVF-embryo transfer, its effectiveness is similar to daily i.m. injections. In oocyte donation the ring provides a progestative milieu which improves the implantation rate and eliminates the discomfort of daily i.m. injections.

Comparison of ultrasonography and hysteroscopy in the diagnosis of intrauterine lesions in infertile women.

STUDY OBJECTIVE: To compare the effectiveness of transvaginal ultrasound versus hysteroscopy in the diagnosis of benign intrauterine lesions, with histology as the gold standard. DESIGN: Retrospective study (Canadian Task Force classification II-1). SETTING: Unit of Reproductive Medicine, Department of Obstetrics and Gynecology of Clinica Las Condes, Santiago, Chile. PATIENTS: Infertile women who had undergone complete fertility evaluation. INTERVENTION: Transvaginal ultrasound, hysteroscopy, and histologic evaluation of endometrial samples performed in all 126 women. MEASUREMENTS AND MAIN RESULTS: The most frequent condition was a normal cavity (59.5%), followed by endometrial polyps (34.9%) and fibromyomas (3.9%). Synechiae and bone metaplasia were extremely rare. Sensitivity of transvaginal ultrasound for the diagnosis of endometrial polyps was 95.6% compared with 89.9% for hysteroscopy (NS). Specificity was 97.4% with transvaginal ultrasound versus 93. 3% with hysteroscopy (NS). Positive and negative predictive values were similar for both methods. CONCLUSION: Transvaginal ultrasound is as effective as hysteroscopy in diagnosing benign intrauterine lesions. It could be the first clinical diagnostic test in the investigation of the uterine cavity.

Fetal prognosis in varix of the intrafetal umbilical vein.

To assess the clinical significance of varix of the intraabdominal portion of the umbilical vein, we reviewed 10 cases diagnosed prenatally by ultrasonography at a median gestational age of 27 weeks. A comprehensive anatomic survey and serial follow-up scans were performed in each case. All three fetuses with associated anomalies died in utero, and prenatal karyotyping revealed that two of them had a chromosomal abnormality. In six of the seven cases with structurally normal fetuses the pregnancy proceeded uneventfully, and no neonatal complications were attributed to the umbilical vein varix. Our experience and the review of the literature revealed 42 cases with information on fetal outcome. Overall, 24% of the fetuses died, 12% had a chromosomal abnormality, and 5% developed hydrops. We conclude that fetuses with varix of the intrafetal umbilical vein should be considered at risk for poor outcome. However, if no other anomalies are present, the prognosis is generally good.

The empty follicle syndrome: a pharmaceutical industry syndrome.

The purpose of this study is to provide evidence that empty follicle syndrome (EFS) is a result of an abnormality in the in-vivo biological activity of some batches of commercially available human chorionic gonadotrophin (HCG). This is a comparative study between six consecutive in-vitro fertilization (IVF) cases with EFS (study group) and 10 IVF pregnancy cycles (control group). Both groups received the same ovarian stimulation protocol consisting of leuprolide acetate and human menopausal gonadotrophin (HMG). An i.m. injection of 10,000 IU of HCG was administered once follicles had reached 18-20 mm and oestradiol/follicle > or = 16 mm was at least 900 pmol/l. Transvaginal aspiration was performed 36 h later. Plasma HCG prior to and 12 h after i.m. injection as well as the follicular fluid (FF) concentrations of oestradiol, progesterone, luteinizing hormone (LH) and HCG were determined in the study group and controls. The in-vitro biological activity of the batch of HCG used by the EFS cases and the control group was determined using a Leydig cell preparation from adult rats. Furthermore, the plasma clearance rate after i.v. injection of 5000 IU of HCG, from the same batches, was studied in three male volunteers. In the IVF cycles, no HCG was detected in plasma prior to the injection of commercial HCG. After 12 h, no HCG was detected in the study group compared to a mean of 207.5 IU/l (110-360) in controls. Mean FF concentration of LH, HCG, progesterone and oestradiol was 0.9 IU/l, 0 IU/l, 3.1 nmol/ml and 4.4 nmol/ml in EFS compared to 1.0, 98.3, 32.0 and 3.7 in pregnancy cycles. The in-vitro biological activity in both HCG batches was not significantly different; however, immunoreactive HCG used in EFS cases was undetectable in plasma of male volunteers as soon as 10 min after i.v. injection of 5000 IU of HCG. The endocrine abnormalities found in follicular fluids of EFS are not a consequence of an ovarian problem but the result of a lack of exposure to biologically active HCG. The rapid clearance of the drug after i.v. injection and the high affinity of desialylated HCG to liver cells suggest this to be a possible explanation for this infrequent but unfortunate event.

Contribution of the male factor to unexplained infertility: a review.

The more exhaustive the evaluation of couples with unexplained infertility, the more likely is the opportunity for detecting the aetiological factor responsible for infertility. Transport of spermatozoa through the upper genital tract and their ability to fertilize the oocyte are two obscure areas for the conventional evaluation of infertility. Although research in the former area is limited, there is indirect evidence that impaired sperm transport could be one of the causes of infertility in some couples with otherwise unexplained infertility. on the other hand, the availability of sperm function tests and the correlation of their results with in-vitro fertilization rates have allowed the detection of a previously hidden male factor in couples with unexplained infertility. It has been demonstrated that couples suffering unexplained infertility have significantly lower in-vitro fertilization rates in comparison with patients with tubal problems. These results can be explained because of several case control studies in patients with unexplained infertility have reported defects in capacitation and sperm motion characteristics, binding of the spermatozoa to the zone pellucida, acrosome reaction, acrosin activity of the spermatozoa, and the ability of the spermatozoa to penetrate zona-free hamster oocytes. These observations suggest that methods for assessing the fertilizing capacity of the spermatozoa have to incorporated in the evaluation of couples with unexplained infertility in order to amplify the scope of the workup and to better decide the appropriate treatment for these couples.

Predictive value of human chorionic gonadotrophin in the outcome of early pregnancy after in-vitro fertilization and spontaneous conception.

This prospective study analyses the value of the beta-subunit of human chorionic gonadotrophin (beta-HCG) in 120 pregnancies obtained after in-vitro fertilization (IVF)--embryo transfer. Spontaneous conception cycles (n = 16) were also analysed allowing a comparison between these two forms of conception. Of the 120 clinical pregnancies, 48 started as single gestations and 50 started with two or more sacs. There were 14 clinical abortions and eight ectopic pregnancies. All subjects had blood samples taken under a fixed protocol on days 11, 14, 17, 20 and 23 after follicular aspiration. Weekly samples were obtained thereafter until day 60 from ovum retrieval. Transvaginal ultrasounds were performed at weekly intervals, starting on day 23 after follicular aspiration. In spontaneous conception cycles blood samples were obtained daily, starting on the day of follicular rupture. In spontaneous conception cycles and in IVF-embryo transfer conceptions, the doubling time (DT) of beta-HCG was 1.4 +/- 0.3 and 1.6 +/- 0.4 days respectively. This difference was not significant. In multigestations, the DT was 1.5 +/- 0.3 days. The absolute values of beta-HCG in early spontaneous gestations were significantly higher than in IVF-embryo transfer cycles, suggesting that the blastocyst implants with less cellular mass when initiated in vitro as compared with the in-vivo condition. The early prediction of ectopic pregnancy and spontaneous clinical abortion was analysed by the beta-HCG profile as well as the absolute values in comparison to normal pregnancies. Both parameters showed significant differences as early as the interval between days 11 and 23 from follicular aspiration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pregnancy rate in an oocyte donation program.

Oocyte donation programs offer an alternative treatment for infertile women with ovarian failure or abnormal ovarian function. Seventeen cycles of in vitro fertilization and embryo transfer with donated oocytes were performed in 13 women, with a mean age of 34.8 years. The hormonal replacement therapy consisted of a fixed dose of oral estradiol valerate, 6 mg daily, and intramuscular progesterone in oil, 100 mg daily. Estrogen and progesterone were continued for 10 more weeks after embryo transfer if pregnancy was established. After 13 embryo transfers, 8 pregnancies were obtained, for a pregnancy rate per transfer of 61.5%. Today seven pregnancies are progressing normally, including one set of twins. This results suggest that an oocyte donation program using a fixed and simple hormonal replacement therapy is an adequate treatment for these infertile couples.

Intrauterine insemination: critical analysis of a therapeutic procedure.

Donor intrauterine insemination with washed spermatozoa (fresh semen) was performed in 36 women (63 cycles) whose husbands had azoospermia due to primary or secondary testicular failure. Simultaneously a control group of 76 couples (156 cycles) with proven fertility, who had recently discontinued mechanical non-hormonal contraception, were encouraged to have sexual intercourse during the fertile period. The age of the women was similar in both groups and the timing criteria were also similar. The pregnancy rate per woman was 50% in the donor insemination group and 47.4% in the control group (difference not significant). The pregnancy rate per cycle was 28.6% in the artificial insemination group and 23.1% in the control, natural insemination group (difference not significant). The number of artificial or natural insemination cycles required to achieve pregnancy was similar in the study and control groups. This study suggests that when the inseminating spermatozoa and female partner are normal, as occurs in the donor insemination group, intrauterine insemination is as efficient as natural insemination in achieving pregnancy but is not more successful.

Fertilization rate in couples with unexplained infertility.

A group of 24 couples with unexplained infertility was scheduled for in-vitro fertilization and tubal embryo transfer between May 1989 and September 1990. In the same period, in-vitro fertilization and intrauterine transfer of embryos was planned in a control group of 44 women with tubal infertility. The mean age and duration of infertility were similar in both groups and the same scheme of ovarian stimulation was used. No statistically significant difference was obtained comparing oestradiol levels and numbers of mature oocytes retrieved between the group of patients with unexplained infertility and those with tubal infertility. The fertilization rate of the oocytes obtained from women with unexplained infertility (60.4%) was significantly lower (P less than 0.001) than that of the oocytes obtained from patients with tubal infertility (87.3%). There was no statistically significant difference in the cleavage rates between patients with unexplained infertility and those with tubal infertility. It is concluded that lack of fertilization is an unexplored cause of infertility in couples with unexplained infertility.

[Importance of the suture material in the surgery of genuine stress urinary incontinence]. / Importancia del material de sutura en la cirugía por incontinencia urinaria de esfuerzo genuina.

Between July 1978 and November 1985, 73 abdominal operations were performed for the surgical correction of genuine stress incontinence using the Marshall-Marchetti-Krantz technique. Non-absorbable suture materials were used in the vesicourethropexy in 30 case (41%) and absorbable suture materials in 43 cases (59%). A relapse was not observed after two years of follow-up in the group of patients operated on with nonabsorbable suture materials while a relapse of 5% after one month, 14% after six months, 22% after one year and 44% after two years was observed in the group of patients operated on with absorbable suture materials. A statistically significant difference was found between both groups after one year (p = 0.031) and after two years (p = 0.012) of follow up. The postoperative complications were similar in both groups, urinary infection being the most frequent one. We conclude that nonabsorbable suture materials offer definitive advantages with respect to absorbable suture materials in the abdominal surgical correction of genuine stress incontinence.