Antepartum management protocol. Timing and mode of delivery in gestational diabetes.

We sought to determine whether strict glycemic control during diabetic pregnancy combined with elective early induction of labor reduces the rate of cesarean delivery and fetal birth trauma. We used a population-based longitudinal design covering three periods corresponding to changes in the management protocol for diabetic pregnancy at our center: 1) 1980-1989: no set level of maternal glycemia, elective cesarean section when estimated fetal weight was 4,500 g or more, and no elective early induction; 2) 1990-1992: desired mean maternal glycemia < or = 5.8 mmol/l, elective cesarean section when estimated fetal weight was 4,000 g or more, and elective early induction at 40 weeks for large-for-gestational-age fetuses; 3) 1993-1995: desired mean maternal glycemia < or = 5.3 mmol/l, elective cesarean section when estimated fetal weight was 4,000 g or more, and elective early induction at 38 weeks for large-for-gestational-age fetuses. Outcome of diabetic pregnancies was compared for the three periods, relative to that of the normal population. There was a gradual, constant, and significant decline in the incidence of macrosomia (17.9, 14.9, and 8.8%, respectively; P < 0.05) and large-for-gestational-age fetuses (23.6, 21.0, and 11.7%; P < 0.05) coupled with a gradual, nonsignificant decrease in cesarean deliveries (20.6, 18.4, and 16.2%) and in cases of shoulder dystocia (1.5, 1.2, and 0.6%), to rates close to those of the normal population. Our data show that maintaining strict control of maternal diabetes and adhering to an active management protocol for early elective delivery based on the estimated fetal weight have a significant effect on reducing the rate of macrosomia, thereby affecting the incidence of both traumatic births and cesarean deliveries.

Total estradiol, free estradiol, sex hormone-binding globulin, and the fraction of estradiol bound to sex hormone-binding globulin in human follicular fluid.

Sex hormone-binding globulin (SHBG), percent free estradiol (E2), the fraction of E2 bound to SHBG, and total E2 were measured in the serum and follicular fluid of 12 women (25 follicles) who had received gonadotropin stimulation in an in vitro fertilization program. The women were classified as high or low responders based on peak serum E2 levels (high responders: peak E2, greater than 1500 pg/ml; low responders: peak E2, less than 1000 pg/ml). During treatment, serum levels of SHBG increased in high responders from 55 +/- 8.8 (+/- SEM) to 96 +/- 16 nM (P less than 0.01), but did not change in low responders. SHBG was more concentrated in follicular fluids from high responders (142 +/- 12.5 nM) than in those from low responders (44.4 +/- 5.8 nM). A positive correlation was found between serum and follicular fluid levels of SHBG (r = 0.873; P less than 0.01). In follicular fluid, total E2 levels, which varied from 100-2650 ng/ml, correlated (r = 0.790; P less than 0.01) closely with SHBG levels. The percent free E2 averaged 5.9% (range, 4-10.6%) in follicular fluid compared to 1.8% (range, 1.5-2.1%) in serum. An inverse correlation (r = -0.661; P less than 0.01) was found between total E2 concentrations and percent free E2 in follicular fluid. The relationship between serum and follicular fluid levels of SHBG suggests that SHBG in follicles arises from the circulation. Although SHBG is present in follicular fluid in amounts similar to those in serum, the large quantities of E2 in preovulatory follicules exceed the binding capacity for SHBG, and the majority of E2 appears to be bound to albumin. Hence, it seems unlikely that SHBG in follicular fluid regulates estrogen action in ovarian target cells.

Flow cytometric analysis of deoxyribonucleic acid in human granulosa cells from in vitro fertilization cycles: relationships to oocyte maturity and fertilizability and to follicular fluid steroids.

We measured the mitotic activity of granulosa cells, sex steroid concentrations in follicular fluids, and the maturity and fertilizability of oocytes from 49 follicles. Flow cytometric measurements of DNA were used to determine the percentage of cells in G0/G1, S, and G2/M phases of the cell cycle. Mitotic index was designated as the percentage of granulosa cells in S + G2/M. The progesterone concentration and the progesterone to estradiol ratio in follicular fluids were inversely correlated to mitotic index (r = -0.506; P less than 0.001, and r = -0.320; P less than 0.02, respectively). Estradiol and androstenedione levels did not correlate with the mitotic index. The mitotic index was higher in follicles with immature oocytes [25.6 +/- 2.0% (+/- SE); n = 7] than in follicles with mature oocytes (15.6 +/- 1.2%; n = 41; P less than 0.001). The mitotic index of granulosa cells was lowest in follicles with oocytes that fertilized (15.5 +/- 1.8%), higher in follicles with oocytes that remained unfertilized (18.5 +/- 1.3%; P less than 0.03), and highest in follicles with oocytes that fertilized abnormally (24.0 +/- 2.1%; P less than 0.02). Differences in maturity or fertilizability of oocytes were not associated with variations in follicular fluid progesterone concentrations. The study supports the concept that mitotic activity is decreased when granulosa cells become luteinized. During early follicular growth it is assumed that estradiol and perhaps androstenedione may be important regulators of cell division. Our findings suggest that progesterone, perhaps acting as an antiestradiol, is more important in controlling granulosa cell division of preovulatory follicles during the late follicular phase.

Regulation of platelet aggregation and adenosine triphosphate release in vitro by 17beta-estradiol and medroxyprogesterone acetate in postmenopausal women.

Clinical studies have suggested that hormone replacement therapy (HRT) may reduce the risk of coronary heart disease in postmenopausal women. Although progestins are commonly added to HRT preparations for uteroprotection, the perceived beneficial cardiovascular effects of HRT are thought to be mediated predominantly by the estrogen component. Platelets play a critical role in the pathogenesis of atherosclerosis and cardiovascular disease and, hence, it is possible that the cardiovascular effects of estrogens are mediated, at least in part, through inhibition of illicit platelet activation. The aim of this study was to examine the effects of sex steroids on adenosine diphosphate (ADP)-induced platelet aggregation and adenosine triphosphate (ATP) release in vitro in postmenopausal women. In addition, the effects of antiestrogens 14-hydroxy tamoxifen (4-OHT) and ICI 182780] and antiprogestins (RU 486 and ZK 98299) were also investigated. Preincubation of platelet-rich plasma (PRP) with antiestrogens or antiprogestins did not alter subsequent platelet aggregation or ATP release in response to ADP. However, preincubation with 17beta-estradiol (E2) significantly inhibited ADP-mediated platelet aggregation by a mean (+/-SEM) of 37%+/-6% (p = 0.02) and ATP release by 82%+/-6% (p = 0.03), an effect that was reversed by the addition of ICI 182780 or 4-OHT but not RU 486 and ZK 98299. Although the progestin medroxyprogesterone acetate (MPA) also significantly inhibited platelet aggregation (by 28%+/-5%, p = 0.02) and ATP release (by 63%+/-9%, p = 0.02), this inhibition was not reversed by the addition of antiprogestins or antiestrogens. These data show that sex steroids can modulate platelet function in vitro. Furthermore, as platelets are devoid of nuclear components, these findings indicate that estrogens may regulate platelet function through binding to a non-nuclear receptor with ligand-binding properties similar or identical to the wild-type receptor. By contrast, MPA appears to exert its effect through a mechanism that does not involve binding to the "classical" progesterone receptor.

A new procedure for removal of a "lost" intrauterine device.

OBJECTIVE: To evaluate the efficacy of removal of a "lost" intrauterine device (IUD) with the use of a cylindrical brush. METHODS: Women aged 25-43 years with so-called "lost" IUD, in whom the string was indiscernible, were enrolled in the study. During gynecologic examination, a cylindrical brush was rotated in the cervical canal until the device was extracted by a rotating motion. No antibiotics were used after removal of the IUD with the cylindrical brush. RESULTS: Twenty-seven women whose IUD could not be removed from the uterine cavity because of an indiscernible string were referred for a trial of IUD removal. All patients had used a plastic, copper-releasing IUD. Before admission, they had undergone an attempt at IUD removal by their physician using either a hook or clamp. In 24 patients who were referred to our center, the IUD was removed by using a cylindrical brush to view the string. The IUD was removed by hysteroscopy in three cases, in two of which no string was found. CONCLUSION: A cylindrical brush can be used safely as an adjunct to remove an IUD and is a simple method that may be performed before another invasive procedure is attempted.

Thrombosis of the pelvic veins associated with a large myomatous uterus.

BACKGROUND: Deep vein thrombosis is a rare indication for hysterectomy. CASE: A 45-year-old woman presented with a myomatous uterus of 20 gestational weeks' size that was compressing the pelvic veins directly and causing thrombosis. After preparation of the patient with anticoagulants and installation of an umbrella device in the inferior vena cava, we performed an uneventful abdominal hysterectomy. CONCLUSION: Pelvic deep vein thrombosis is a rarely reported complication of myomatous uterus. It can be managed successfully by anticoagulants, placement of an umbrella device in the inferior vena cava, and hysterectomy, as in our case.

Triplet pregnancy in uterus didelphys with delivery interval of 72 days.

A unique case of triplet pregnancy in a woman with uterus didelphys is described, with fetuses A and B in the right uterine horn and fetus C in the left horn. Missed abortion of fetus A was diagnosed in the 22nd week of gestation by real-time ultrasonography, but only in the 27th week of gestation did the right uterine horn contract, resulting in expulsion of fetus A. Fetus B was delivered by cesarean section 2 hours later. Fetus C remained in the left uterine horn until the 37th week of gestation, when a viable 2490-g female infant was delivered by cesarean section. Triplet pregnancy occurs with sufficient frequency to be unremarkable; however, triplet pregnancy in a patient with uterus didelphys and with 72 days' lapse between the delivery of the first 2 fetuses and delivery of the third is a rare occurrence.

Fetal transcerebellar diameter in Down syndrome.

OBJECTIVE: To determine whether cerebellar hypoplasia in Down syndrome is established and clinically recognizable in the second trimester of pregnancy and to evaluate the screening utility of transverse cerebellar diameter measurements for Down syndrome fetuses. METHODS: Ultrasonographic biometry data obtained before genetic amniocenteses on 42 fetuses with Down syndrome and 1161 karyotypically normal fetuses were analyzed. Mean transverse cerebellar diameters stratified by gestational age were compared. A regression equation relating transverse cerebellar diameters to gestational age was calculated for 387 normal fetuses and applied to the remaining normal (n = 774) and all Down syndrome fetuses. Ratios of observed to expected cerebellar diameters were calculated. Sensitivity, specificity, and positive predictive values were calculated for various cutoff points and Down syndrome prevalences. RESULTS: Cerebellar diameters in Down syndrome fetuses were smaller than in normal controls at all gestational ages (P < .005) by an average of 0.67-0.87 mm. A ratio of 0.92 for observed/expected cerebellar diameters yielded a sensitivity of 21%, specificity of 95%, and positive predictive values of 1.66% and 0.56% in populations with a risk for Down syndrome of one in 250 and one in 750, respectively. CONCLUSIONS: Cerebellar hypoplasia is developmentally established and sonographically recognizable in second-trimester Down syndrome fetuses. However, cerebellar size differences between normal and Down syndrome fetuses are too small to be clinically useful.

High-order multifetal gestation--management and outcome.

During the period 1975-1989, 11 high-order (quadruplet or more) multifetal gestations reaching the second trimester were treated in our department. All pregnancies resulted from ovulation induction therapy. Premature contractions occurred in all cases. Two women delivered stillborn quadruplets vaginally at 25 and 26 weeks' gestation. Nine women had cesarean deliveries at 28-35 weeks; one fetus was stillborn and two of the 39 live-born infants died. Twenty-nine (74%) weighed less than 1500 g and 16 (41%) were below the tenth percentile for gestational age. Thirty infants have been followed for at least 2 years, corrected for gestational age; 21 (70%) are developing normally, two are severely handicapped with both cerebral palsy and mental retardation, four have mild motor delay, and three have mild motor and mental delay.

Incidence of abortion in pregnancies after in vitro fertilization and embryo transfer.

Our purpose was to assess factors that are associated with an increased rate of spontaneous abortion in pregnancies initiated by in vitro fertilization. Pregnancies were diagnosed by measurement of serum human chorionic gonadotropin (hCG) 15 days after embryo transfer. Of the 64 women who conceived, 47 delivered term infants, one patient delivered a stillborn at 22 weeks, 14 aborted in the first trimester, and two had pregnancies that implanted in the tube. Abortion rates were similar for women treated with human menopausal gonadotropin (24%; 12 of 54) and those who received clomiphene citrate (12.5%; one of eight). Two patients conceived after treatment with a combination of clomiphene citrate and human menopausal gonadotropin, neither of whom aborted. In 54 patients treated with human menopausal gonadotropin, there were no significant differences in mean maternal age, number of years of infertility before the pregnancy, history of previous pregnancies, amount of human menopausal gonadotropin used to induce ovulation, serum estradiol levels on the day of hCG administration, mean number of follicles, and the mean number of transferred embryos between the group who delivered and the group who aborted. We conclude that none of these factors are associated with increased tendency for fetal loss in our in vitro fertilization program. Beta-hCG levels on day 15 after embryo transfer were significantly lower in the group who aborted than in the group who delivered, and may be predictive of implantation failure.

Cytokines--involvement in reproduction.

OBJECTIVE: To relay the current knowledge on the interaction between the immune and reproductive systems that results from sharing certain lymphohematopoietic cytokines and their receptors. DATA IDENTIFICATION: Major studies related to this topic have been identified through MEDLINE searches and through the published literature. STUDY SELECTION: Those that have reported on the role of cytokines in the neuroendocrine events of reproduction, ovarian function, placenta, and the developing embryo. RESULTS: The field of growth factor and cytokines and their effects on reproduction is a rapidly growing new area of investigation. Immune cells and related cytokines have been shown to affect the neuroendocrine events of reproduction, ovarian function, placenta, and the developing embryo. Furthermore, it is now becoming apparent that these relationships are reciprocal in that the different cellular components of the neuroendocrine and reproductive systems and the developing embryo can modulate the production of cytokine by the immune system and can also produce certain cytokines. The presence of lymphocytes and macrophages in the female reproductive system, together with the fact that these cells may secrete soluble factors influencing embryo development and trophoblast growth, might suggest that cytokines may play a fundamental role in the mechanisms of immunological reproductive failure. In addition, different mixtures of these mediators, generated by immune cells, the developing embryo, or other maternal cells, may modulate the fine tuning of these activities. CONCLUSIONS: Current knowledge indicates a close interaction between the immune and reproductive functions. Further understanding of these interactions may lead to new concepts in fertility regulation.

Pharmacokinetics of follicle-stimulating hormone: clinical significance.

OBJECTIVE: To review studies that examine the pharmacokinetics and pharmacodynamics of endogenous, as well as several exogenous FSH preparations. DESIGN: Related studies were identified through a computerized bibliographic search. PATIENTS: Initial pharmacodynamic studies were done in animal models and in women and men with either hypogonadotropic hypogonadism or suppressed hypothalamic-pituitary-gonadal axis. More recent studies evaluated FSH pharmacokinetics during ovulation induction treatment in women with normal ovulatory cycles or polycystic ovarian syndrome. RESULTS: Various types of FSH exist according to their sialic acid content. High estrogen levels induce the secretion of less sialylated molecules with higher receptor affinity and an increased clearance rate. It appears that there is a threshold FSH level that should be reached to achieve an ovarian response. A very narrow range exists between the threshold and ceiling level for monofollicular growth. This threshold level is surpassed intentionally during IVF treatment cycles to induce multiple follicular recruitment. The threshold level can change under situations such as polycystic ovaries, perimenopause, oral contraceptives, and GnRH analogue treatment. CONCLUSIONS: To avoid the risk of ovarian hyperstimulation syndrome and multiple pregnancies, careful adjustments of serum FSH levels should be made by fine dosage modifications. By monitoring FSH levels and using less sialylated preparations, the efficacy of the treatment probably will improve.

A comparative prospective study of conventional regimen with chronic low-dose administration of follicle-stimulating hormone for anovulation associated with polycystic ovary syndrome.

OBJECTIVE: To compare efficiency of conventional and chronic low-dose regimens for treatment of anovulation associated with polycystic ovary syndrome (PCOS). DESIGN: Fifty participants divided into two equal groups. The first group was treated with urinary human FSH using a conventional stepwise protocol and the second group was treated with a regimen of chronic low-dose and small incremental rises with urinary human FSH or with recombinant human FSH for a maximum of three cycles. SETTING: Tertiary referral university hospital fertility unit. PATIENTS: Fifty infertile women with clomiphene citrate-resistant anovulation associated with PCOS. MAIN OUTCOME MEASURES: Pattern of follicular development, amount of FSH required, serum E2 concentrations, cycle fecundity, cumulative conception, and live birth rates. Multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) rates. RESULTS: Compared with the conventional dose protocol, the chronic low-dose regimen yielded slightly improved pregnancy rates (40% versus 24%) while completely avoiding OHSS and multiple pregnancies, which were prevalent (11% and 33%, respectively) with conventional therapy. Monofollicular development was induced in 74% versus 27% of cycles, and the total number of follicles > 16 mm and E2 concentrations were half those observed on conventional therapy. CONCLUSIONS: For women with PCOS, a chronic low-dose regimen of FSH eliminated complications of OHSS and multiple pregnancies while maintaining a satisfactory pregnancy rate. This modality, thus, has distinct advantages and could well replace conventional gonadotropin therapy for these patients.

Laparoscopic unwinding of twisted ischemic hemorrhagic adnexum after in vitro fertilization.

We present a case where, for the first time, unwinding of ischemic hemorrhagic adnexum was performed successfully through the laparoscope without the need to operate. Aspiration of ovarian fluid before detorsion facilitates the procedure; follow-up showed spontaneous follicular growth. We conclude that laparoscopic detorsion of ischemic adnexum is feasible. Apparently, oocytes are not damaged by the torsion and the ovary resumes normal function. This procedure should be considered in women during the reproductive age and in every case where malignancy can be ruled out.

Differences in ovarian stimulation in human menopausal gonadotropin treated woman may be related to follicle-stimulating hormone accumulation.

Two groups of normal ovulatory women who displayed either a marked (high responders; HR) or a more subtle (low responders; LR) ovarian response to a fixed dose of human menopausal gonadotropins (hMG) were evaluated for differences in blood levels of hormones. Serum follicle-stimulating hormone (FSH) levels doubled during the first 3 days of treatment (to approximately 20 mIU/ml) in all patients; thereafter, the levels plateaued in LR but continued to rise steadily (to 35 mIU/ml) in HR. In the latter group, rise in estradiol (E2) and FSH was accompanied by an increase of luteinizing hormone (LH; two to five times) progesterone (P; four to eight times) testosterone (T; three to four times) and prolactin (PRL; 2 times) toward the end of the follicular phase. Positive correlation was found between FSH and E2 in HR and LR. Positive correlation was found, however, between LH, T, and P and between E2, P, and PRL only in HR. The extent of FSH accumulation in the circulation may be a principal factor in determining an individual's response to hMG therapy. Temporal changes of blood hormones indicated that the continuous rise in FSH levels in HR was associated with early luteinization of the follicles. Increased secretion of P in the follicular phase of these women (HR) probably synergized with the elevated E2 levels to elicit LH release. Similar changes in blood hormones were not found in LR.

Treatment-independent pregnancy after in vitro fertilization and embryo transfer trial.

This study indicates that SP occur in a higher percentage than theoretically expected after IVE-ET treatment, but it is not conclusive as to whether the SP is independent or a result of the treatment or operative laparoscopy. Our results are in agreement with those of previous studies that have shown that SP occur with almost all kinds of infertility. We therefore reject the previous suggestion of Steptoe, who argued that to prevent ectopic pregnancy from complicating embryo replacement, preparatory electrocauterization of diseased tube should be performed. We also suggest that as long as the results of treatment are below the normal monthly spontaneous conception rate, there is justification for a prospective random study that includes all diagnoses other than BTB. Such a study might help make any future selection of patients for treatment more appropriate.

Intravenous immunoglobulin treatment for recurrent abortions caused by antiphospholipid antibodies.

There is an association between the presence of antibodies that bind to anionic phospholipids and the occurrence of repeated spontaneous abortion. Many uncontrolled studies have reported favorable pregnancy outcome in women treated with steroids, low-dose aspirin, heparin, or their combination. Similarly, treatment failures have been reported with most of these therapeutic regimens. Immunoglobulins play a central role in immune regulation. A wide spectrum of human diseases are associated with decreased or abnormal regulation of Ig levels. Recently, IV preparations of Ig have become available for clinical use, including treatment of patients with recurrent abortions and high levels of antiphospholipid antibodies. The effectiveness of this new mode of therapy can be related to several immunological mechanisms such as blockade of antibody binding to receptors on macrophages, increase in T suppressor cells, or decrease in antibody synthesis. The latter effect may be mediated by anti-idiotypic antibodies in the Ig preparation. Determination of dosage of IV Ig, duration of treatment, and treatment intervals are all empirical in patients with recurrent abortions and high levels of antiphospholipid antibodies because antiphospholipid antibody levels are not useful for monitoring therapy. Although the data available at present are promising, additional randomized trials are needed to determine the efficacy of IV Ig in patients with immunological recurrent abortions.

Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy.

A series of 201 cycles of ovarian hyperstimulation syndrome (OHSS) in 154 women were reviewed. Pregnancy occurred in 75 of 201 cycles. Twelve pregnant women (16%) presented with torsion of hyperstimulated ovary, but only 3 out of 126 patients (2.3%) who did not conceive had torsion. Because diagnosis of adnexal torsion is usually uncertain and surgical intervention is likely to be delayed, these infertile women risk losing their ovaries. The clinical picture of torsion of adnexa in patients with OHSS is presented here. The combination of ovarian enlargement, abdominal pain, nausea, progressive leukocytosis, and anemias might indicate torsion of adnexa. Although during operation the adnexa appears dark, hemorrhagic and ischemic, we suggest that it can be saved by simply unwinding it. In 11 such cases intraoperative unwinding of the adnexa was performed, and in 8 patients it was the only operative procedure. No postoperative complications were noted and in all the cases the ovaries were proven functional by ultrasonography. We concluded that torsion of hyperstimulated adnexa in patients who conceived after gonadotropin therapy, is a special entity that requires more attention to achieve early diagnosis. Nevertheless even with delayed diagnosis, the ovary can still be saved.

Ovarian hyporesponsiveness in combined gonadotropin-releasing hormone agonist and menotropin therapy is associated with low serum follicle-stimulating hormone levels.

The study was designed to evaluate if ovarian hyporesponsiveness, which is associated with combined gonadotropin-releasing hormone agonist (GnRH-a) and human menopausal gonadotropin (hMG) therapy is because of suboptimal serum follicle-stimulating hormone (FSH) levels. Two groups of 12 patients each were suppressed with GnRH-a and stimulation with a fixed dose of hMG. The control group (n = 10) received equal doses of hMG only. The follicular phase and the number of hMG ampules was significantly higher in the study group. Basal FSH levels and FSH levels during hMG treatment were significantly lower in patients treated with GnRH-a. Peak estradiol levels and the outcome of in vitro fertilization treatment were similar in the three groups. We suggest that the delay in ovarian response in patients treated with a combination of GnRH-a and hMG is because of lack of endogenous contribution of FSH, resulting in low circulating levels of FSH. An increase of serum FSH levels by administration of higher doses of hMG can reverse this effect.

In vitro fertilization and embryo transfer in well-controlled, insulin-dependent diabetics.

Five IDD patients achieved strict preconception glycemic control and then underwent nine IVF-ET cycles. All patients had high E2 response with an adequate number of preovulatory oocytes retrieved and normal fertilization and cleavage rates; one conceived. Follicular fluid analysis revealed similar E2, P, A, hCG, PRL, and IGF-I levels to non-IDD controls. The source of the insulin detected in the FF of IDD patients was probably from the insulin doses administered intensively during the tight diabetes management; insulin was absent in non-IDD participants. It seems that patients with IDD have conventional responses to gonadotropin stimulation for IVF and their follicular milieu resembles that of non-IDD patients. Nevertheless, in view of the significant advantages of preconceptional diabetes control in regard to pregnancy outcome, they should be allowed to participate in IVF programs only after tight preconception metabolic control has been obtained.