Vaginal bleeding and early pregnancy outcome in an infertile population.

OBJECTIVE: Our purpose was to determine the prognostic value of vaginal bleeding in early pregnancy outcome as well as to analyze the role of cardiac activity in predicting pregnancy viability in the presence of vaginal bleeding. STUDY DESIGN: This was a cohort study of pregnancies obtained using either assisted reproductive technology (ART) or routine infertility treatment (RIT). Two hundred twenty-eight pregnant women were divided into two groups based on the presence or absence of vaginal bleeding. Successive measurements of beta-hCG levels were obtained every 2 days, starting on day 14 after ovulation or embryo transfer. All pregnancies underwent weekly transvaginal ultrasound (UTZ) examinations beginning on day 21. The occurrence of vaginal bleeding was monitored weekly. RESULTS: Seventy of the 228 patients (31%) had bleeding in early pregnancy, resulting in 31 (44%) pregnancy losses. Only 22 pregnancy losses (14%) were observed in 158 patients who did not have bleeding (P < 0.001). The abortion rate for the bleeding versus nonbleeding groups was 35 and 9%, respectively (P < 0.001). Vaginal bleeding was associated with a higher abortion rate in pregnancies following RIT than ART (51 vs 8%; P < 0.001). Fetal cardiac activity was noted by vaginal ultrasound in 189 patients. In this subpopulation, bleeding was also associated with a higher abortion rate than that in the nonbleeding group (17 vs 4%; P < 0.001). However this higher incidence was observed only in pregnancies following RIT, not ART (28 vs 5%; P < 0.001). CONCLUSIONS: Although bleeding significantly decreased the chance of a normal pregnancy outcome, more than 50% of the pregnancies did progress to term. The presence of cardiac activity in this population as a sign of fetal viability offered a better pregnancy prognosis. However, the predictive value of fetal cardiac activity was reduced in the presence of vaginal bleeding in an infertile population treated with RIT.

Desogestrel.

Desogestrel is a new, potent progestogen with very low androgenic properties. When used as a contraceptive, it is a strong antiovulatory compound, even at low doses. The clinical efficacy is as good as that of the old progestogens. It has a low incidence of side effects and complications, similar to other progestogens. It may have a role as an anti-androgen in women with hyperandrogenic symptoms in need of adequate oral contraception.

PIP: A new generation of progestogens was developed in response to perceived drawbacks of the classic oral progestogens, especially their inherent androgenic effect and concern over the negative effect upon plasma lipids and the possible clinical consequences of the described changes. The new progestogens had to confer the high levels of contraceptive effectiveness achieved with the old oral contraceptives, while maintaining a low incidence of side effects. Desogestrel is one of these new, potent progestogens with very low androgenic properties. It has been used in some countries for more than a decade, but only recently in the US. The author describes desogestrel's chemical composition and metabolism, metabolic effects, biologic activity, availability, and clinical studies on cycle control, contraceptive effectiveness, side effects, anti-androgenic effects, and use in peri-menopause. When used as a contraceptive, desogestrel is a strong antiovulatory compound, even at low doses, with clinical efficacy as good as that of the old progestogens. There is a low incidence of side effects and complications with use of the compound. Moreover, desogestrel may have a role as an anti-androgen in women with hyperandrogenic symptoms in need of adequate oral contraception.

Successful pregnancy outcome after cryopreservation of all fresh embryos with subsequent transfer into an unstimulated cycle.

OBJECTIVE: To assess the pregnancy outcome of freezing and storing all fresh embryos produced in a stimulated IVF cycle and replacing them in a subsequent nongonadotropin-stimulated cycle. DESIGN: Retrospective study. SETTING: University-associated assisted reproductive technology program. PATIENTS: We studied 36 patients (age range 23 to 44 years) who underwent cryopreservation of all fresh embryos in a controlled ovarian hyperstimulation (COH) cycle because of either the risk of severe ovarian hyperstimulation (24 patients, group 1) or the presence of an endometrial lining < 8 mm in thickness (12 patients, group 2). Five hundred fifty-five embryos were generated for replacement in 63 cycles. All embryos were cryopreserved in 1.5 M propanediol at the pronuclear or two-cell stage, and 264 embryos subsequently were transferred into a hormone replacement cycle (70%) or natural ovulatory cycle (30%). The average number of embryos transferred per patient was 4.2. RESULTS: Twenty-one clinical pregnancies were achieved, giving a pregnancy rate (PR) of 58.3% per patient (33.3% per cycle). The live birth rate was 50% per patient (28.6% per cycle). The implantation rate was 9.1%. Groups 1 and 2 had a similar PR per patient (58.3%). With 208 cryopreserved embryos remaining and considering the 33.3% PR per cycle, we expect the overall extrapolated PR to be 63.9%. CONCLUSIONS: This is the first series showing that freezing and storing all fresh embryos produced in a stimulated IVF cycle and replacing them in a subsequent nongonadotropin-stimulated cycle results in successful PRs. These results underlie the importance of a successful cryopreservation program in IVF and could be a possible approach to overcoming the alleged adverse effects of COH on the endometrium, thereby improving the chances of pregnancy when numerous embryos are obtained simultaneously.

Relationship between serum estradiol concentration and IGF-I, IGF-II and IGF-binding proteins in patients with premature ovarian failure on short-term estradiol therapy.

OBJECTIVE: Insulin-like growth factors (IGFs) exert stimulatory effects on follicular growth and development, and early embryogenesis. In view of this, we studied the effect of short-term estradiol treatment, as used in preparing the uterus for embryo implantation, on the serum concentrations of IGFs and their binding proteins (IGFBP) in patients with premature ovarian failure (POF). PATIENTS AND METHODS: Twenty-four patients with POF, enrolled in an assisted reproduction program, were treated with increasing doses of estradiol up to 8 mg daily for 6 weeks. Blood was sampled for measurement of serum estradiol, IGF-I, IGF-II, and IGFBP 1, 2 and 3 at various times during estradiol treatment. RESULTS: There was no significant correlation between serum estradiol concentrations and the serum concentrations of IGF-I and IGF-II. As expected, IGF-I and IGF-II concentrations in serum correlated positively with the serum concentration of IGFBP-3, the major IGF-binding protein in serum. CONCLUSION: The results of this study suggest that estradiol therapy as used to prepare the uterus for implantation has no significant effect on serum IGF-I and IGF-II concentrations, and therefore probably does not influence, via an IGF-mediated mechanism, the success of implantation and early embryonic development.

Outcome of triplet pregnancies after assisted reproductive techniques: how frequent are the vanishing embryos?

OBJECTIVE: To assess the incidence of spontaneous embryo reduction as well as the obstetric and neonatal outcome of triplet gestations after assisted reproductive techniques (ART). METHODS: We analyzed the spontaneous outcome of 38 pregnancies in which three gestational sacs were identified with vaginal ultrasound between 21 and 28 days after ART. Weekly follow-up visits were scheduled during the first trimester until referral to a high-risk obstetrician. After delivery, each patient was interviewed individually and, if necessary, the obstetrician was contacted. RESULTS: The triplets delivery rate was 47.4%, whereas 31.6% delivered twins, 18.4% delivered singletons, and only one patient miscarried all three cases (2.6%). Finding three fetal heart beats was associated with a triplet delivery rate of 69.2%, a twin incidence of 19.2%, and a singleton birth rate of 11.6%. Embryo resorptions were observed mainly during the first 7 weeks of gestation and did not occur beyond the 14th week. The mean gestational age at delivery and neonatal birth weight were significantly lower among triplets (32.8 weeks and 1,740 g versus 35.3 weeks and 2,352 g in twins and 39.1 weeks and 3,122 g for singletons). Triplets had a 100% prematurity and cesarean section rate compared with 67% and 75% in twins and 0% and 43% in singletons, respectively. Hospitalization at the Neonatal Intensive Care Unit was required in 83% of newborn triplets, 29% of twins, and 0% of singletons, with a mean stay of 34 and 21 days for triplets and twins, respectively. One stillbirth and no neonatal deaths were reported, with an overall perinatal mortality rate of 11.9 per 1,000. CONCLUSIONS: Spontaneously, approximately 50% of triplet pregnancies will experience at least one embryo resorption. The ongoing triplets demand a complex and more expensive perinatal management, a strong argument to consider limiting the number of oocytes-embryos transferred in ART.

Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies.

OBJECTIVE: To evaluate the clinical usefulness of thyroid antibodies in determining early pregnancy outcome. SETTING: University-based facility at the Center for Reproductive Health, University of California, Irvine. PATIENTS: Four hundred eighty-seven infertile patients that successfully conceived with assisted reproductive techniques from January 1991 to December 1992. INTERVENTIONS: An enzyme immunoassay for semiquantification of thyroglobulin (TG) and thyroid peroxidase antibodies used to determine antibody status from stored serum of these patients. MAIN OUTCOME MEASURE: Thyroid antibody status in early pregnancy. RESULTS: Of the 487 patients studied, there were 106 women who were antibody positive for anti-TG, antithyroid peroxidase, or both, and 381 who were negative. The overall incidence of positivity was 22%. In the antibody-positive group there was a 32% clinical miscarriage rate in comparison to 16% in the antibody-negative group. This did reach statistical significance. There was no significant difference between the two groups in the incidence of biochemical or ectopic pregnancies. There also was no significant difference between the groups in age, gravidity, or number of prior pregnancy losses. CONCLUSION: In our patient population, thyroid antibodies proved to be a useful marker for identifying women at risk for clinical miscarriage but they appear not to have an association with biochemical pregnancies.

Effect of freezing on the relative escape force of sperm as measured by a laser optical trap.

OBJECTIVE: To determine the possible effect of freezing on sperm escape force as measured by laser trap. DESIGN: Controlled clinical study. SETTING: Normal volunteers, academic setting. PATIENTS: Normal, healthy volunteers. INTERVENTION: Sperm selection, freezing and thawing. Measurement of relative (sperm) escape force before and after freezing. MAIN OUTCOME MEASURE: Comparison of escape force as a measurement of freezing effects. RESULTS: Wide individual variations noted, with some individuals showing significant increases or decreases. The relative escape force in fresh (76.1 +/- 31.1 mW) and in frozen-thawed samples (75.6 +/- 40.0 mW) were similar. CONCLUSION: Freezing does not affect the relative escape force of normal sperm. Any possible detrimental effect of freezing on sperm may be related to other sperm functions.

[Correlation between plasma progesterone and ultrasonographic detection of corpus luteum in ovulatory cycles]. / Correlacion entre progesterona plasmatica y deteccion ultrasonografica de cuerpo luteo en ciclos ovulatorios.

The ultrasound detection of corpus luteum in the midluteal phase of ovulatory cycles was associated with significantly higher levels of plasma progesterone, opposed to those patients where a corpus luteum could not be identified. The hormone level was directly proportional no the number of corpora lutea seen. However, only 33.3% o patients with no corpus luteum visible were found to have suboptimal plasma progesterone levels (< 10 ng/ml).

Is there a role for ovarian stimulation and intra-uterine insemination after age 40?

The objective of this study was to determine the conception rate in infertile couples in which the female partner was > or = 40 years old and who had received ovarian stimulation treatment and intra-uterine insemination (IUI). It was a retrospective study of 77 patients who underwent a total of 210 treatment cycles. Protocols for ovulation induction included clomiphene citrate, human menopausal gonadotrophin (HMG) and clomiphene citrate plus HMG. Patients were monitored using transvaginal ultrasound, and two IUI were performed 24 and 48 h after the determination of urinary luteinizing hormone (LH) surge or human chorionic gonadotrophin (HCG) injection. A total of 11 pregnancies were reported, giving a pregnancy rate of 14% per patient and 5% per cycle. Eight spontaneous abortions occurred, giving a pregnancy wastage of 73%. In a previous comparative analysis of 543 patients < 39 years old receiving IUI and identical protocols of ovarian stimulation, 141 pregnancies were achieved, giving a pregnancy rate of 21% per patient and 10% per cycle. The miscarriage rate in that group was 18%. This report compares IUI results for women > or = 40 years with those obtained previously for younger women, and shows the very poor success rate in women > 40 years of age. This information will be important in the proper counselling of this group of patients, as well as indicating that a prompt recommendation for assisted reproductive treatment should be made soon after the failure of a few attempted cycles of ovarian stimulation treatment and IUI.

The predictive value of a single beta human chorionic gonadotropin in pregnancies achieved by assisted reproductive technology.

OBJECTIVE: To investigate whether a single serum beta-hCG in pregnancies achieved by assisted reproductive technologies (ART) can accurately predict pregnancy viability and, in viable pregnancies, multiple gestation. DESIGN: Four hundred sixty-one consecutive successful ART pregnancies were studied retrospectively. Seventy-one of the 461 patients were excluded because their beta-hCG was either drawn on the incorrect day or outside our facility. Three hundred ninety subjects had a serum beta-hCG drawn 14 days after ET or 16 days after gamete transfer. The beta-hCG samples were analyzed by immunoradiometric assay based on the Third International Reference Standard (IRS) (First International Reference Preparation (IRP)). Pregnancy status was followed, at minimum, through the first trimester. RESULTS: One hundred fifty (38%) of the 390 were found to be nonviable, resulting in spontaneous abortion (n = 38, 10%), ectopic pregnancy (n = 27, 6%), or biochemical pregnancies (n = 85, 22%). A statistically significant difference by the Scheffe F-test was found between the mean beta-hCG value of the nonviable (115 mIU/mL) (conversion factor to SI unit, 1.00) and viable (428 mIU/mL) pregnancies. The positive predictive value of a single beta-hCG > 100 mIU/mL in distinguishing viable from nonviable pregnancies was 0.83 (sensitivity 91%, specificity 71%). Of the 240 viable pregnancies, 74 (32%) were multiple gestations (57 twins, 14 triplets, and 3 quadruplets). The mean beta-hCG of the singleton pregnancies (266 mIU/mL) was significantly different from that of the multiple gestations (792 mIU/mL). The positive predictive value of a single serum beta-hCG < or = 400 mIU/mL in distinguishing singleton from multiple gestations was 0.92 (sensitivity 86%, specificity 82%). CONCLUSION: A single early serum beta-hCG may be used in ART pregnancies to predict which pregnancies will continue beyond the first trimester and to identify multiple gestations. Early reassuring tests may reduce anxiety.

Comparison between nafarelin and leuprolide acetate for in vitro fertilization: preliminary clinical study.

OBJECTIVE: To evaluate the clinical effect of two different biochemical GnRH agonists (GnRH-a), nafarelin acetate and leuprolide acetate (LA), as adjunct to induction of ovulation in patients for IVF. DESIGN: Twenty-four women were assigned randomly to either nafarelin acetate or LA during IVF cycles. SETTING: University-affiliated clinics. PATIENTS: Infertile women undergoing IVF cycles in an academic research environment. INTERVENTIONS: Intranasal nafarelin at a dosage of 200 micrograms twice daily or LA at a dose of 1 mg/d SC was administered. Blood samples were collected on day 21 of previous cycle, days 2 and 8, and before hCG injection. MAIN OUTCOME MEASURE: Patient response as indicated by follicular phase serum levels of E2, FSH, and LH. RESULTS: Hormone profiles on cycle day 2 showed no statistical difference between both GnRH-a groups in FSH levels and a slight statistical difference for E2 levels. Patient response as demonstrated by follicular phase of E2, FSH, and LH measured on cycle day 8 and the day of hCG injection showed no statistically significant difference in both groups. Furthermore, the mean number of follicles, eggs retrieved, egg quality, fertilization rate, and number of embryos transferred and frozen were similar. The cycle cancellation rate and pregnancy rate per stimulation start were also not statistically different between the two groups. CONCLUSION: The study shows the comparable efficacy of these two drugs in controlled ovarian hyperstimulation (COH) protocols. The easy administration of nafarelin with prompt nasal absorption and the readily achieved blood level made nafarelin an option for use in COH in assisted reproductive technology.

Frozen zygote intrafallopian transfer: a successful approach for transfer of cryopreserved embryos.

OBJECTIVE: To assess whether frozen ET to the fallopian tube is a possible alternative for cryopreserved embryos. DESIGN: Fifty-four patients (mean age 35 years) participated, in which their embryos were cryopreserved in 1.5 M propanediol at the pronuclear or two-cell stage. Each patient then underwent a steroid replacement cycle consisting of oral micronized 17 beta-E2 2 mg on days 2 to 4, 4 mg on days 5 to 7, 6 mg on days 8 to 10, and 8 mg from day 11 on. Serial ultrasounds were performed to evaluate the endometrium until an optimal thickness of > or = 10 mm triple layer was achieved. At this time, 100 mg IM progesterone was initiated and the zygote intrafallopian transfer (ZIFT) procedure was performed on the third day of P administration. The average number of embryos transferred was 4.4. RESULTS: Twenty-two clinical pregnancies resulted, giving a pregnancy rate of 41%. Eight miscarriages occurred and one ectopic pregnancy resulted, giving a live birth rate of 24%. Implantation rate was 10.8%. The highest chance of pregnancy was seen in patients who never had a previous IVF, GIFT, or ZIFT (61%). CONCLUSION: This is the first report of a series of frozen ETs to the fallopian tubes. These results indicate that tubal transfer may offer a protective benefit of the tubal environment and avoidance of endometrial trauma, and should be added to our armamentarium of replacing cryopreserved embryos.

The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome.

Previous experiences in subjects with other forms of third space fluid accumulation have shown that albumin is efficacious in preventing and correcting haemodynamic instability. Using a similar approach in an effort to increase the serum oncotic pressure and to reverse the leakage of fluids from the intravascular space, high risk subjects for severe ovarian hyperstimulation syndrome (SOHS) were treated with albumin. In a recent large study two high risk factors were identified, i.e. the number of oocytes and levels of serum oestradiol. Thirty-six women undergoing assisted reproductive techniques who presented both these factors, received intravenous albumin at a dose of 5% in Ringers lactate in doses of 500 ml during oocyte retrieval and 500 ml immediately thereafter in the recovery room. Daily measurements of urine output, serum and urine electrolytes, weight, abdominal girth, and haematocrit prior to and after oocyte retrieval revealed normal serum and urine electrolyte levels, and no signs of haemoconcentration. No patient in this study developed SOHS, and of course none had to be hospitalized. Vaginal ultrasound performed in the majority of the subjects revealed < or = 100 ml of peritoneal fluid 48-72 h after oocyte retrieval. The only complication from the use of intravenous albumin was the appearance of a 'flu-like condition' (low grade temperature, nausea and muscle pains) developed by 12 women between days 3 and 5 after oocyte collection. Intravenous albumin had thus prevented the development of severe ovarian hyperstimulation syndrome in an assisted reproduction programme.(ABSTRACT TRUNCATED AT 250 WORDS)

Should oral contraceptives be sold over-the-counter?

PIP: The US Food and Drug Administration (FDA) is considering reclassifying oral contraceptives (OCs) as an over-the-counter (OTC) drug. Family planning providers do not agree on whether making OCs an OTC drug would hurt or benefit US women. Since OC use currently requires a physician's approval, some providers believe that OCs are geographically, economically, and often culturally inaccessible to many women. Others feel that OTC status would result in incorrect use and an increase in unplanned pregnancies. Some argue that giving OCs OTC status would increase access to adolescents and low-income women, and therefore reduce unwanted pregnancies. Yet, Medicaid pays for OCs but not OTCs. Low-income women already have access to OCs at reduced rates at family planning clinics. If OCs achieve OTC status, FDA needs to come up with a way for pharmacies, other sales outlets, and labels to provide the instructions and counseling about nuisance and serious side effects once supplied by clinicians. This would be difficult because instructions are extensive and complex. The fact that 1 in 8 people in the US is illiterate makes it hard to provide adequate instructions on labels. Consequences of improper use are substantial: unwanted pregnancy, psychological stress, health risks from an abortion, risk of mortality from childbirth. Women might stop having the routine gynecological examinations now required for the prescription, so clinicians would not be able to screen for contraindications, sexually transmitted diseases (STDs), and AIDS or provide advice about condom use to prevent STDs and AIDS. This effect would adversely affect public health. Industry is concerned about increased liability if women do not use OCs correctly. Industry is largely staying out of the debate, however. Others are concerned that OTC OCs would cost more to market. A pilot model program is needed to determine whether reclassification would improve access and long-term maintenance on OCs. More research is needed before FDA grants OCs OTC status.^ieng

Melatonin and gonadotropin secretion after acute exercise in physically active males.

Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone, testosterone (T) and melatonin were measured in seven physically active male volunteers after exercise on a treadmill using the Bruce protocol. Measurements were made on blood samples obtained before exercise, within 30 s after exercise, at 15 min after exercise, and subsequently at 30-min intervals after exercise for a total duration of 180 min. Serum LH concentration fell from a peak post-exercise level of 15.7 (4.7) IU.l-1 [mean (SD)] to a nadir of 10.3 (2.4) IU.l-1 (P < 0.004). Nadir values in individual volunteers were seen between 60 and 150 min after exercise. This fall in serum LH was paralleled by a similar fall in the concentration of serum T. Serum melatonin concentrations did not change significantly after exercise. It is concluded that melatonin, despite is reported anti-gonadotropic properties, does not play a role in the depression of serum LH after acute strenuous exercise in physically active males.