Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study.

BACKGROUND: In-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger. METHODS: We conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015. RESULTS: Significant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section. CONCLUSION: Excessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.

Empty follicle syndrome: successful treatment in a recurrent case and review of the literature.

Empty follicle syndrome is a condition in which no oocytes are retrieved after an apparently adequate ovarian response to stimulation and meticulous follicular aspiration. It is a rare condition of obscure etiology. A patient with primary infertility who underwent seven assisted reproductive technique cycles is described. In spite of a satisfactory ovarian response, aspiration yielded no oocytes in four cycles and 1-4 low quality oocytes in three cycles. In the index treatment cycle, ovulation was triggered using GnRH agonist 40 h prior to ovum pickup and hCG was added 6 h after the first trigger. Eighteen oocytes were recovered, of which 16 were mature and were inseminated by ICSI. Two embryos were transferred 48 h after aspiration and nine embryos were cryopreserved. The patient conceived and delivered a healthy boy at 38 weeks of gestation. The literature is reviewed and possible etiologies and treatment options of this enigmatic syndrome are suggested.

Should the modified natural cycle protocol for frozen embryo transfer be modified? A prospective case series proof of concept study.

OBJECTIVE: Modified natural cycles for frozen embryo transfer utilize an ovulation trigger which assists in embryo transfer scheduling and simplifies cycle monitoring. There have been conflicting results with this protocol and modifications may be sought. We wanted to ascertain whether a modified natural protocol for frozen embryo transfer without triggered ovulation but with luteal progesterone support disconnecting the timing of embryo transfer from the timing of the LH surge can achieve a high pregnancy rate. STUDY DESIGN: Candidates for frozen embryo transfer of 48-h cleavage cell embryos were recruited from May 2016 to April 2018. The patients were monitored for endometrial growth, follicle formation and estradiol, progesterone, and LH hormone levels. After meeting the predetermined criteria, embryo transfer was scheduled. The patients began progesterone treatment 48 h before embryo transfer, regardless of identification of the LH surge if ovulation had not commenced. The predetermined primary outcome was the biochemical pregnancy rate while the secondary outcome included the clinical pregnancy rate and the ongoing pregnancy rate. Patients were monitored to the eighth week of pregnancy, but data was collected from the medical records to provide the live birth rate as well. RESULTS: Fifty-six women were screened. Eleven women declined or did not meet the inclusion criteria. Three had anovulatory cycles and were excluded. Forty-two women were included in the statistical analysis. The implantation rate was 42.9 % [95 %CI 29.3 %-56.4 %). Of the 42 participants, 25 (59.5 %) conceived [95 % CI 44.0 %-75 %]. Two pregnancies ended in first trimester miscarriage leaving 23 (54.7 %) ongoing pregnancies [95 % CI 39.1 %-70.5 %]. One patient experienced a late abortion such that the live birth rate was 22 of 42 patients or 52.4 % [95 % CI 36.4 %-68.0 %]. CONCLUSION: The proposed modified natural protocol which utilizes progesterone luteal support but does not trigger ovulation, maintains a high pregnancy rate while providing flexibility regarding the day of transfer disconnected from the day of the LH surge. This was a prospective, proof of concept study. This protocol may be suitable for smaller or public in-vitro fertility units whose resources are limited and facilities are not available daily. The high pregnancy and live birth rate that we found provides confidence that this protocol can be part of the armament of protocols the clinician may offer to his patients. Larger studies should confirm these findings.

Two-day IUI treatment cycles are more successful than one-day IUI cycles when using frozen-thawed donor sperm.

The difference in pregnancy rates following intrauterine insemination (IUI) for 1 vs. 2 days in the periovulatory period has been reported as either inconsequential or favoring the use of two consecutive inseminations, 24 hours apart. Our study compared the monthly fecundity and cumulative probability of pregnancy in a large group of women (n = 123) undergoing controlled ovarian hyperstimulation and 1- or 2-day inseminations with donor sperm prepared from frozen-thawed samples. All patients underwent controlled ovarian hyperstimulation employing either clomiphene citrate in 217 cycles or human menopausal gonadotropin in 185 cycles. The choice of single or double insemination was decided by the day of the week each patient received human chorionic gonadotropin for ovulation induction. Approximately 80% of all the patients underwent both single and double insemination treatments during the 2.5-year study period. Ninety-three patients received single inseminations in 180 cycles, whereas 103 patients received double inseminations in 222 cycles. Nine clinical pregnancies were achieved in the 1-day group (5% per cycle, 9.7% per patient), while 39 pregnancies occurred in the 2-day group (17.9% per cycle, 37.9% per patient). Two and five spontaneous abortions occurred in the 1- and 2-day groups, yielding take-home baby rates of 3.9% per cycle (7.5% per patient) and 15.3% per cycle (33.0% per patient), respectively. The cumulative probability of conception over 15 cycles of treatment was consistently twice as high or higher for the 2-day group. The results of this study support the use of 2-day IUI treatment cycles when using frozen-thawed donor sperm.

Induction of pre-ovulatory gonadotrophin surge with gonadotrophin-releasing hormone agonist compared to pre-ovulatory injection of human chorionic gonadotrophins for ovulation induction in intrauterine insemination treatment cycles.

The clinical outcome of intrauterine insemination (IUI) treatment cycles employing a gonadotrophin-releasing hormone agonist [GnRHa, triptorelin (Decapeptyl)] or human chorionic gonadotrophin (HCG) for ovulation induction was compared. A group of 48 patients presenting with amenorrhoea, oligomenorrhoea or unexplained infertility were all treated with human menopausal gonadotrophins (HMG) from day 5 of the cycle, on an individualized schedule. They were then randomly divided into two groups to receive either a single s.c. injection of 0.1 mg triptorelin or a single i.m. injection of 10,000 IU HCG after follicular maturation. IUI was performed approximately 24 and 48 h following the injection. A transitory increase in serum luteinizing hormone and follicle stimulating hormone concentrations was achieved following injection of GnRHa. A total of 24 patients received 72 treatment cycles with GnRHa, producing 11 conceptions (15.3%) and two abortions (18.2%), resulting in a term pregnancy rate of 13.6%. There were four cases of grade 3-4 ovarian hyperstimulation syndrome (OHSS), two of which were conception cycles. In all, 24 patients underwent 68 cycles treated with HCG, producing 18 conceptions (26.5%) and six abortions (33.3%), resulting in a term pregnancy rate of 19.0%. There were eight cycles of grade 3-4 OHSS, two of which were conception cycles. These results show that an s.c. injection of a relatively low dose of GnRHa can be as effective as HCG in producing pregnancy in IUI treatment cycles.

A random single Doppler study of the umbilical artery in the evaluation of pregnancies complicated by diabetes.

To evaluate a random single Doppler study of the systolic to diastolic ratio of the umbilical artery as a predictor of perinatal outcome in diabetic pregnancies, a prospective double-blind study was performed in 92 diabetic pregnant women between 28 and 40 weeks of gestation. Main outcome measures were perinatal outcome: group A, normal outcome; group B, poor outcome. The sensitivity and specificity of the Doppler studies as a predictor of poor perinatal outcome were 39% and 92%, respectively. The positive and negative predictive values were 54% and 86%, respectively. Our results suggest that the systolic to diastolic ratio of the umbilical artery offers no advantage over other well-established tests in the management of diabetic pregnancies.

Gonadotrophin-releasing hormone agonist compared with human chorionic gonadotrophin for ovulation induction after clomiphene citrate treatment.

The objective of this study was to compare hormonal response, luteal phase adequacy and pregnancy and abortion rates in patients randomized to receive human chorionic gonadotrophin (HCG) or gonadotrophin-releasing hormone agonist (GnRHa) during ovulation cycles stimulated by clomiphene citrate. Anovulatory patients received either one s.c. dose of tryptorelin (0.1 mg; n = 104) or one i.m. dose of HCG (10,000 IU; n = 106) after clomiphene citrate stimulation had induced enlarged ovarian follicles (> 17 mm in diameter). A short-lived, transitory increase in serum luteinizing hormone (98 +/- 9 IU/l) and follicle-stimulating hormone (30 +/- 5 IU/l) concentrations was measured at 12 h following the injection of GnRHa, and these concentrations returned to baseline levels by 36 h post-injection. Midluteal progesterone concentrations were similar in both groups (> 10 ng/ml), and the mean luteal phase duration was also not significantly different (13 days). There were no significant differences in the mean number of pregnancies (12.0 versus 12.6% per cycle) and the abortion rate (18.2 versus 12.5%) between the GnRHa- and HCG-treated groups respectively. There were no complications related to treatment in either group. The results show that a relatively low dose of GnRHa can be used in place of HCG to induce ovulation in clomiphene citrate-treated patients.

Induction of pre-ovulatory luteinizing hormone surge by gonadotrophin-releasing hormone agonist for women at risk for developing the ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is a major risk in patients undergoing ovulation induction protocols. Withholding injection of human chorionic gonadotrophin (HCG) may prevent the development of OHSS, but can also result in failure to ovulate and conceive. We have used a gonadotrophin-releasing hormone agonist (GnRHa) as an alternative to HCG in women not undergoing in-vitro fertilization in an attempt to prevent OHSS. The study included 12 cycles in 12 women scheduled for ovulation induction with human menopausal gonadotrophin (HMG) who were at risk of developing OHSS (oestradiol > 3500 pg/ml, number of follicles > 20). GnRHa was injected to induce the pre-ovulatory, luteinizing hormone surge which triggers follicular maturation. Progesterone was administered for luteal support. Six pregnancies were achieved, and none of the 12 women developed OHSS. Since the pregnancy rate in this study was acceptable, we can recommend the use of GnRHa instead of HCG in any case at risk of developing OHSS.

The effect of ejaculatory frequency on semen characteristics of normozoospermic and oligozoospermic men from an infertile population.

The characteristics were examined of 87 consecutive semen samples obtained from participants of an intra-uterine insemination (IUI) programme. The population investigated comprised 65 normozoospermic, 13 moderately oligozoospermic and nine severely oligozoospermic individuals. The samples were produced after 4 days abstinence for the first IUI and after a further day of abstinence for the second IUI. Semen volume, sperm concentration, total sperm count and total motile sperm count for the whole population decreased significantly between the first and second samples. The characteristics of the second sample were significantly decreased only for the normozoospermic group.

Management of functional ovarian cysts after induction of ovulation. A randomized prospective study.

To investigate the need for hormonal treatment in patients with functional ovarian cysts after induction of ovulation, a randomized prospective study was performed. Fifty-four patients who were found to have ovarian cysts after induction of ovulation were randomly assigned to two groups: a) Treatment with estrogen/progesterone. b) Expectant management. The main outcome measure was resolution of ovarian cysts. There was no significant difference between the groups. We conclude that hormonal treatment is not necessary in cases with functional ovarian cysts after induction of ovulation.

Superovulation and intrauterine insemination in the treatment of male factor infertility.

Recent studies report that superovulation combined with intrauterine insemination (IUI) is more successful than superovulation alone, IUI alone or superovulation with intracervical insemination in couples with male subfertility. Our study evaluated two superovulation protocols in the management of male factor infertility using IUI: (A) clomiphene citrate and human chorionic gonadotropin (HCG) and (B) human menopausal gonadotropin and HCG. Fifteen couples with severe oligoasthenozoospermia (OAS) were treated with protocol A in 54 cycles, and no pregnancies were achieved. Eight of the 15 couples with severe OAS subsequently received protocol B for 24 cycles and elicited no pregnancies. Thirty-seven couples with moderate OAS received protocol A for 169 cycles, and 2 pregnancies ensued (5.4% per couple and 1.12% per cycle). Twelve of the 35 nonpregnant couples with moderate OAS then received protocol B for 31 cycles, and 4 pregnancies were recorded (33.3% per couple and 12.9% per cycle).

Exogenous estrogen therapy concurrent with clomiphene citrate--lack of effect on serum sex hormone levels and endometrial thickness.

The antiestrogenic action of clomiphene citrate (CC) is claimed to have an adverse effect on the development of the secretory endometrium. This effect can be assessed: (1) sonographically by measuring endometrial thickness, and (2) by serum hormone levels. The aim of this study was to evaluate whether administering ethinyl estradiol (EE) during CC treatment has any effect on endometrial thickness and/or hormone levels. Seventeen patients were treated with CC for one cycle and with CC plus EE in an adjacent cycle either before or after. The patients were followed by daily assessment of endometrial thickness, follicular growth and serum estradiol levels as well as midluteal prolactin and progesterone levels. We did not find any significant difference in either endometrial thickness, estradiol level, midluteal prolactin or progesterone levels between the two treatment protocols. We conclude that exogenous EE, in the dosage used in this study, does not overcome CC-induced alterations in endometrial thickness.

Cervical leukocytosis and abnormal post-coital test: a diagnostic and therapeutic approach.

Inflammatory processes and cell-mediated immunological reactions in the cervix and vagina have been implicated as causal factors in some cases of infertility. This investigation examined whether cervical Papanicolaou (PAP) smears in combination with post-coital tests could reveal infertile patients with asymptomatic cervical leukocytosis. Women (n = 56) attending a hospital-based community infertility clinic were subjected to post-coital tests and simultaneous preparation of cervical PAP smears. Those women (n = 18) with both abnormal post-coital tests and asymptomatic cervical leukocytosis, based on abnormally high numbers of leukocytes in the PAP smear, were randomly divided into two groups. One group (n = 10) received antibiotic therapy and the other (n = 8) received no therapy. In the treated group six women became pregnant within 3 months after treatment; none of the eight untreated patients became pregnant within the same period. These results suggest that cervical PAP smears, in cases with abnormal post-coital tests, are useful in detecting couples whose infertility may be due to simple, undetected, asymptomatic bacterial infections.

Factors associated with withdrawal bleeding after administration of oral dydrogesterone or medroxyprogesterone acetate in women with secondary amenorrhea.

The effectiveness of two treatment regiments in inducing withdrawal bleeding in secondary amenorrhea was compared and correlated with the endometrial thickness and endogenous E2 and progesterone concentrations. A prospective, randomized and double-blind study was designed at the Outpatient Clinic of Reproductive Endocrinology, Central Emek Hospital, Afula, Israel. Seventy-seven premenopausal women with oligomenorrhea or amenorrhea, 48 of whom qualified for the study, underwent a 5-day course of either medroxyprogesterone acetate (MPA) 5 mg b.i.d. or dydrogesterone (DG) 10 mg b.i.d. Endogenous pretreatment values of E2 and progesterone and endometrial thickness (by transvaginal ultrasonography) were correlated with the bleeding response. Withdrawal bleeding occurred in 93% of women taking either MPA or DG. Side effects occurred similarly among the groups. Lipid concentrations were unchanged. Endogenous E2 and progesterone were limited predictive value for withdrawal bleeding. Endometrial thickness as measured by transvaginal sonography correlated significantly with the bleeding response.