Neonatal assessment of babies conceived by in vitro fertilization.

PROBLEM: Neonatal outcome of in vitro fertilization (IVF) pregnancies has been described by different authors, but several issues have yet to be resolved. The aim of the present study was to evaluate neonates conceived in vitro and to direct special attention to neonatal morbidity and prevalence of minor abnormalities. The information that has been accumulated so far is scant. METHOD: The first 100 babies conceived in vitro, and subsequently born in our institute, were investigated and compared with the general, spontaneously conceived newborn population. All infants were examined by a senior neonatologist, and the data that were recorded included gestational age at delivery, birth weight, gender, major malformations, minor congenital abnormalities, neonatal mortality, and neonatal morbidity (including asphyxia, jaundice, meconium aspiration, hypoglycemia, and hypocalcemia). RESULTS AND CONCLUSIONS: The data indicate that the IVF neonates assessed had a higher rate of low birth weight (37%), twinning (30%), and preterm birth (20%) in comparison with the general reference population (p < 0.05). However, no differences were encountered either in the rate of small for gestational age infants or the incidence of major malformations and minor abnormalities between these groups of newborns. The overall neonatal morbidity in IVF babies was found to exceed that of the general population. Nevertheless, at birth, there were no clinical pathognomonic signs typical of IVF babies, although more detailed metabolic, endocrine, and neurobehavioral studies are still required to confirm that newborns conceived in vitro do not differ from those conceived spontaneously in any of these respects.

Augmentation of low ovarian response to superovulation before in vitro fertilization following priming with contraceptive pills.

Poor ovarian response to superovulation treatment is observed in a certain group of patients, the so-called 'low responders'. Despite the evolution of sophisticated controlled ovarian hyperstimulation (COH) regimens prior to the in vitro fertilization (IVF), the ideal stimulation protocol for the low responder has yet to be formulated. The objective of this study was to assess the effect of oral contraceptive pills (OCP), administered before the initiation of superovulation, on ovarian response and IVF treatment results in patients with previous 'low response' to exogenous gonadotropin stimulation. The study group comprised 42 patients who had exhibited poor ovarian response to standard superovulation protocols in at least two previous consecutive treatment attempts. Contraceptive pills were administered for 28-42 days and were immediately followed by menotropin treatment. The study group (n=50 cycles) was compared with the control group consisting of previous cycles (n=88) of the same women. Significant differences were noted in peak estradiol levels (983 +/- 739 vs. 517 +/- 249 pg/ml; P <0.01, paired Student's t test) and number of pre-ovulatory follicles between the study and the control groups. Thirty-three of the cycles (66%) reached the stage of ovum pick-up, compared with 22 (25%) of the previous IVF cycles in these women. The mean number of oocytes retrieved was 6.1 +/- 3.0 and 2.4 +/- 1.3 in the study and control groups, respectively (P <0.01; paired Student's t test). Embryo transfer (ET) was performed in 62% of the treatment cycles and resulted in five clinical pregnancies (16.1% per ET). No pregnancies were recorded in the control group. This study demonstrates the beneficial effect of OCP given prior to IVF treatment, and provides an efficient treatment modality for women who consistently respond poorly to standard COH protocols.

The management of dermoid cysts--a comparative study of laparoscopy and laparotomy.

The aim of our study was to compare laparoscopy with laparotomy for the removal of ovarian dermoid cysts. Thirty-eight women with benign ovarian dermoid cyst were allocated for either laparoscopy (18 patients) or laparotomy (20 patients). The two groups were compared for operative and hospitalization times and postoperative course. Operating time was longer (93.6 +/- 23.8 min) and hospitalization time significantly shorter (22.4 +/- 6.6 h) in the laparoscopy group. No complications were reported in either group. We conclude that operative laparoscopy is a safe procedure for the removal of dermoid ovarian cysts and is as effective as laparotomy.

Pregnancy outcome in renal allograft recipients in Israel.

The literature contains reports of 2,309 pregnancies in some 1,600 women who have undergone renal transplantation. Certain pre-pregnancy factors, especially hypertension, renal graft dysfunction and short interval between transplant and pregnancy, appear to increase the neonatal risks. We describe the outcome of 42 pregnancies in 27 allograft recipients at Beilinson Medical Center in Israel during the last 8 years. All were treated with combination immunosuppression regimens. The average interval from time of transplantation to conception was 3.7 +/- 0.4 years (2 months to 9 years). Rejection episodes occurred in 37% prior to pregnancy but in none during or immediately after pregnancy. Of the 42 pregnancies 28% ended in therapeutic or spontaneous abortions, and 29 of the 30 deliveries ended in a life birth. The prematurity rate (65%) was similar to that described in the literature. Renal deterioration was evident in seven women (26%) within 2 years after delivery. Despite this significant success rate, pregnancy in organ transplant patients should still be considered high risk.

Perinatal complications following gestational diabetes mellitus how 'sweet' is ill?

OBJECTIVE: We tested the effect of patient compliance, fasting plasma glucose on oral glucose tolerance test, maternal body constitution, and the method of treatment (diet versus insulin) on the perinatal outcome of patients with gestational diabetes mellitus. STUDY DESIGN: A prospective population-based study compared the perinatal outcome of patients with gestational diabetes mellitus (n = 470) (diabetic with regard to the parameters specified above) and a contemporaneous control group (nondiabetic, n = 250). RESULTS: The diabetic and control groups were matched in demographic characteristics. Patient compliance reduced the rate of macrosomia (14.4%) and neonatal hypoglycemia (3.4%) but not to the levels of the control group (5.2% and 1.2% respectively, p < 0.05). The level of fasting plasma glucose on the oral glucose tolerance test had no effect on perinatal outcome. Intensified (insulin) treatment reduced the rate of macrosomia and large-for-gestational age infants in the subgroups with intermediate and high levels of fasting plasma glucose on the oral glucose tolerance test (9.5%/14.2% and 12.2%/24.2% respectively), again not to levels of the control group (5.2%/10.8%). Obese patients were found to have more perinatal complications than lean patients. Intensified (insulin) treatment has proved to be beneficial in terms of reducing the rate of perinatal complications in the obese patients, but not to the corresponding levels of the control group. Such treatment had no effect on the lean patients. CONCLUSIONS: Strict control of maternal hyperglycemia and high patient compliance are imperative for an effective reduction of perinatal complication in patients with gestational diabetes mellitus. The desired plasma glucose level in the glycemic control of these patients should be further reduced, thus bringing the rate of perinatal complications to that of the normal population.

Microalbuminuria as an early marker of severity in hypertensive pregnant women.

The value of microalbuminuria in predicting hypertensive complications in pregnant patients at high risk was tested in a prospective trial. A total of 276 patients were studied (142 in the study group vs 134 controls). Albumin was measured in 8-h overnight urine collection throughout pregnancy using radioimmunoassay technique. The pregnant women, in both the study and control groups demonstrated a statistically significant increase in albumin excretion rate in the second and third trimester compared with the first. Using logistic and linear regression models, the presence of microalbuminuria in the early third trimester was proven to be predictive of severe disease (odds ratio 2.1, confidence interval (CI) 1.26-3.53) and birth weight (R2 = 0.7, P < 0.05) in the study group. Intrauterine growth retardation and neonatal outcome were less predictable. With the introduction of radioimmunoassays, we believe severe disease can be predicted by detecting microalbuminuria in the early third trimester of pregnancy in high risk patients.

Microalbuminuria in early pregnancy in normal and high-risk patients.

The albumin excretion rate (AER) is elevated in normal pregnant women in the third trimester of pregnancy, compared to the second and first trimesters, and to the non-pregnant state. The effect of early pregnancy on AER values was tested in normal and high-risk pregnant patients using radioimmunoassay. All pregnant patients demonstrated significantly higher AER values as compared to non-pregnant women, and the results were in correlation with higher urinary creatinine clearance values. The appearance of microalbuminuria in the first trimester can indicate underlying renal damage in patients at high risk of hypertensive complications.

Microalbuminuria as an early predictor of hypertensive complications in pregnant women at high risk.

The value of microalbuminuria in predicting hypertensive complications in pregnant patients at high risk was tested in a prospective trial. A secondary aim was to compare the urinary albumin excretion rate between high risk hypertensive pregnant patients (study group) and pregnant patients at high risk of other complications, normal pregnant subjects, and nonpregnant subjects. Over the last 5 years, 276 patients were studied (142 in the study group v 134 controls). Albumin was measured in an 8-hour overnight urine collection throughout pregnancy using a radioimmunoassay technique. The pregnant women in both the study and control groups demonstrated a statistically significant increase in albumin excretion rate in the second and third trimesters compared with the first. Mean albumin excretion rate values were significantly higher in the study group (P = 0.0001). Using logistic and linear regression models, the presence of microalbuminuria in the early third trimester was proven to be predictive of hypertensive complications (odds ratio, 2.1; confidence intervals, 1.26 to 3.53) and birth weight (R2 = 0.7, P < 0.05) in the study group. Intrauterine growth retardation and neonatal outcome were less predictable. With the introduction of radioimmunoassays and in light of these significant clinical results, we believe that high-risk patients in whom abnormal proteinuria develops usually have a microalbuminuric phase weeks earlier, and this test has some predictive value for severe disease. In addition, the accepted definition of gestational proteinuria should be reconsidered.

Viscosity and refractive index of follicular fluid in relation to in vitro fertilization.

PURPOSE: To set the standard values of follicular fluid viscosity and refractive index, and to investigate a possible relationship between these physiological parameters and the outcome of in vitro fertilization treatment. DESIGN AND RESULTS: 128 samples of follicular fluid were collected from 40 in vitro fertilization patients. Viscosity determinations (centipoise; mean +/- SD) for shear rates of 23, 46, 115, and 230 were 2.04 +/- 0.86, 1.84 +/- 0.49, 1.48 +/- 0.27, and 1.38 +/- 0.22, respectively. The average (+/- SD) refractive index was 1.030 +/- 0.002. There was no significant difference between the values of thawed frozen fluids and fresh samples of the same specimens. The data showed no correlation between follicular fluid viscosity or refractive index and the presence of oocytes, their maturation grade or their fertilizing capacity. CONCLUSIONS: For the first time, values of the viscosity and refractive index of follicular fluid obtained during in vitro fertilization have been determined. However, these preliminary results did not reveal any relationship between the physiological parameters examined and the outcome of in vitro fertilization treatment.

The impact of GnRH agonist and menotropin therapy on lipoprotein metabolism.

Two groups of women, 48 undergoing controlled ovarian hyperstimulation for in vitro fertilization (IVF) treatment with a gonadotropin-releasing hormone (GnRH) analog and human menopausal gonadotropin daily and a group of 15 treated with a GnRH analog using the 'luteal phase protocol' before the hyperstimulation for IVF, took part in a prospective randomized study at the IVF Unit of the Beilinson Medical Center, Israel. The aim was to evaluate the changes in lipid metabolism occurring in the course of a standard controlled ovarian hyperstimulation protocol during IVF treatment cycles by measuring serum lipid levels before and after treatment. In the former group, in parallel with the 17 beta-estradiol increase, the cholesterol and low-density lipoprotein-cholesterol levels dropped and the high-density lipoprotein-cholesterol levels increased significantly. The resultant atherogenic index demonstrated a statistically significant decrease. In the latter group the mean lipoprotein levels were slightly different after treatment, but no statistically significant difference was observed. Our results indicate that the GnRH analog alone, administered for 10-12 days, does not induce any significant change in serum lipid levels. When using a combination of a GnRH analog and menotropins, the change of lipoprotein levels is favorable.

Intranasal nafarelin versus buserelin (short protocol) for controlled ovarian hyperstimulation before in vitro fertilization: a prospective clinical trial.

The aim of this study was to compare the effect of nafarelin acetate with that of buserelin acetate nasal spray, when administered in a 'short' protocol, as an adjunct to human menopausal gonadotropin (hMG) for controlled ovarian hyperstimulation before in vitro fertilization (IVF). Twenty-two IVF subjects were randomly recruited. Each underwent two consecutive treatment cycles; one with buserelin (900 micrograms/day) and another with nafarelin (400 micrograms/day). The treatment protocol included transnasal gonadotropin-releasing hormone (GnRH) analog from the second cycle day and hMG from the fourth day of the cycle. The buserelin and nafarelin cycles did not differ significantly in the following parameters: baseline hormone profile, duration of GnRH analog treatment, mean hMG dose required, peak estradiol levels, number of preovulatory follicles, number of aspirated oocytes, fertilization rate and number of transferred or frozen embryos. No side-effects or cancellations of treatment were recorded. The average dose required was lower for nafarelin and, because this analog was given only twice a day, it was more convenient to administer. These findings suggest that nafarelin is as effective as buserelin (when administered in a "short' protocol) in achieving controlled ovarian hyperstimulation. It even offers advantages over buserelin with respect to the total dose required (which probably reflects its relatively high potency) and the subjects' compliance.

The effect of surgical castration on lipid metabolism in premenopausal and postmenopausal women.

OBJECTIVE: To investigate the effect of endogenous estrogen on lipid and lipoprotein metabolism in premenopausal and postmenopausal women. DESIGN: Prospective randomized study. SETTING: Department of Obstetrics-Gynecology, Beilinson Medical Center and Tel-Aviv University Medical School, Israel. SUBJECTS: Twenty-seven women, 15 premenopausal and 12 postmenopausal, undergoing surgical castration (total abdominal hysterectomy and bilateral salpingo-oophorectomy). METHOD: Blood samples were drawn before the surgical intervention and after a 6-month interval. MAIN OUTCOME MEASURES: Assays were performed for estradiol, luteinising hormone and follicle-stimulating hormone, and triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol and total cholesterol/HDL as well as HDL/LDL ratio. RESULTS: No significant differences were found in both groups, before castration and after 6 months. A modest, but statistically significant, rise in triglycerides was observed in the premenopausal group. CONCLUSIONS: The serum lipid and lipoprotein profile encountered in premenopausal and postmenopausal women were unchanged 6 months after surgical castration. The clinical significance indicates that the effect of endogenous estrogen on lipid metabolism is doubtful and should be further investigated.

The effect of medroxyprogesterone acetate and clomiphene citrate on platelet function in menopausal women.

OBJECTIVE: We sought to determine if antiestrogens such as clomiphene citrate (CC) and medroxyprogesterone acetate (MPA) affect platelet activity in postmenopausal patients before and after treatment with estrogens. METHODS: Using an incubation study, we analyzed the effects of CC and MPA on adenosine diphosphate and adrenaline-induced platelet aggregation and on the release of adenosine triphosphate in postmenopausal patients, using a platelet study, we analyzed the effect of these drugs on platelet function. RESULTS: Platelets were inhibited by MPA and CC in the incubation study but not significantly affected in the platelet study. Platelets previously incubated with estrogen were less inhibited by CC than by MPA. DISCUSSION: Thus, platelet study to determine the optimal combination therapy for menopausal patients has indicated that CC has a non-significantly less beneficial in vitro effect on platelet function than MPA.

Placental isoferritin as a marker of early abortion in pregnancies induced by in vitro fertilization.

The relatively high rate of early pregnancy loss in artificial reproductive technology-induced conceptions has driven researchers to seek for an efficient diagnostic tool for estimating the gestational risk in these cases. Monitoring early gestation normalcy using serial beta-human chorionic gonadotrophin (beta hCG) measurements requires several days before diagnosis can be established. The objective of this study was to determine whether placental isoferritin (PLF) can be used as a predictive marker of normal pregnancy development during early stages of in vitro fertilization (IVF)-induced pregnancy. Ninety-three consecutive IVF cycles were investigated. Blood samples for PLF (enzyme linked immunosorbent assay; ELISA) and beta hCG (radio-immunoassay; RIA) determination were obtained from all women on days 11, 13 and 15 following embryo transfer. Placental isoferritin was detectable in the serum 11 days after embryo transfer in IVF conception cycles. These levels were significantly higher in normally developing pregnancies (n = 18) than in cases which eventually aborted spontaneously (n = 9) during the first trimester (mean +/- s.d.; 33 +/- 28 U/mL as compared with 1 +/- 2 U/mL; P = 0.0004; Wilcoxon test; sensitivity 94.5 per cent, specificity 88.9 per cent, positive predictive value 89.9 per cent, negative predictive value 94.5 per cent). Moreover, in those patients who later aborted, lower than normal PLF levels were detected long before the decline in beta hCG titres was evident. Considering its suppressor activity, it is expected that PLF levels would be high at the initiation of normal pregnancy. This may explain the present finding of low PLF levels in abnormally developing IVF-induced pregnancies. These preliminary data suggest that PLF can be used as a sensitive marker for detecting those cases destined to abort at a very early stage. However, further studies are still required on spontaneous conceptions, before this test can be recommended for routine clinical application.

The initial flare-up induced by gonadotropin releasing hormone agonist may serve as a predictor of ovarian response in the current IVF-ET treatment cycle in normogonadotropic women aged 40-48 years.

OBJECTIVE: Our purpose was to assess the potential role of the baseline hormone profile in combination with the initial pattern of response to gonadotropin releasing hormone (GnRH) analogue in predicting ovarian function and hence reproductive outcome in normogonadotropic patients aged 40 years or older undergoing IVF treatment. PATIENTS AND METHODS: A retrospective analysis of 394 controlled ovarian hyperstimulation (COH) cycles that reached the stage of oocyte retrieval was conducted. The study included 163 normogonadotropic (serum FSH < or = 15 IUIL) patients aged between 40 and 48 years who had regular menstrual cycles. Superovulation was achieved using menotropins in combination with GnRH analog (short protocol, beginning on menstrual day 2). The ovarian response was monitored on the third cycle day, the day following the first GnRH analogue administration. RESULTS: Cycle distribution by patient age was 175 (44.4%), 122 (30.9%), and 97 (24.7%), while the patient distribution was 85 (52.2%), 48 (29.5%), and 30 (18.3%) for age groups 40-41, 42-43, and 44-48 years, respectively. The mean total dose of menotropins needed for optimal COH was 1787 IU (range, 600-6000 IU). This dose increased with age, while the yield of oocytes and embryos declined (P < 0.05; ANOVA). A positive correlation was demonstrated between the E2 level on day 3 (GnRH analogue flare effect) and the outcome of the treatment cycle (number of oocytes and embryos). Using multiple stepwise regression analysis, it was demonstrated that the initial (day 3) serum E2 levels, combined with baseline FSH levels, patients's age and body mass index enabled early prediction of the ovarian response in the current IVF-ET treatment cycle (oocytes = 8.2 - 0.18 x Age + 0.17 x BMI - 0.12 x FSH + 0.0042 x E2). CONCLUSIONS: Multiple-parameter analysis demonstrated that the use of the initial E2 response to GnRH analogue stimulation combined with basic clinical data may assist in the prediction of ovarian function and hence the reproductive outcome in normogonadotropic IVF patients aged 40 years or older. This may serve as a clinical tool for improving patient selection and treatment outcome in IVF-ET.

The impact of D-Trp6 LH-RH on plasma lipid levels.

BACKGROUND: There is increasing evidence regarding the correlation between the risk of death from cardiovascular disease and low levels of HDL-cholesterol or high plasma concentrations of LDL-cholesterol, total cholesterol, and triglycerides. Gonadotropin releasing hormone (GhRH) analogues are widely used in assisted reproduction programs. Therefore, it seems important to evaluate possible changes in serum lipoprotein levels following treatment with these compounds. PURPOSE: Our purpose was to assess possible lipoprotein changes following administration of the long-acting GnRH analogue, D-Trp6 luteinizing hormone-releasing hormone (LH-RH). DESIGN: Serum levels of cholesterol, HDL-cholesterol, LDL-cholesterol, and triglicerydes were determined before and after 6 weeks of treatment. RESULTS: No significant changes in either cholesterol or HDL-cholesterol, LDL-cholesterol, or triglicerydes following treatment with D-Trp6 LH-RH were demonstrated in the group of 25 patients investigated. CONCLUSIONS: Short-term use of D-Trp6 LH-RH is not associated with any significant change in plasma lipid levels. Further studies are still required with patients undergoing repeated treatment cycles, especially those who exhibit elevated pretreatment plasma lipid levels, to confirm the long-term safety of GnRH analogues with respect to lipid metabolism.

Diabetic nephropathy and pregnancy: the effect of ACE inhibitors prior to pregnancy on fetomaternal outcome.

BACKGROUND: Diabetic nephropathy is associated with an increase in perinatal mortality and morbidity in uncontrolled pregnant patients. Recently angiotensin-converting enzyme inhibitor (ACE-I) was shown to improve the disease status in non-pregnant subjects. The purpose of this study was to examine the effect of prepregnancy treatment of insulin-dependent diabetes mellitus (IDDM) nephrotic women with captopril angiotensin converting enzyme inhibitor (ACE-1), on maternal renal function throughout pregnancy and on the fetomaternal outcome. METHODS: Eight IDDM nephrotic patients planning pregnancy were treated with captopril for a minimum of 6 months prior to conception together with intensive insulin management. Conception was allowed when proteinuria was < 500 mg/day and euglycaemia was achieved. At conception captopril was discontinued. RESULTS: At the beginning of captopril treatment, proteinuria was 1633 +/- 666 mg/day. At conception, proteinuria dropped to 273 +/- 146 mg/day (P = 0.0000) and increased gradually over the three trimesters to 593 +/- 515, 783 +/- 813, and 1000 +/- 1185 mg/day respectively (P = 0.2 between the trimesters); declining to 619 +/- 411 mg/day (P = 0.0002 vs conception) 3 months after delivery. Only in two patients (25%) did proteinuria exceed 1000 mg/day during pregnancy. There was no significant change in any of the other renal function tests: CCT, serum creatinine, uric acid, K+ and blood pressure. However, there were three cases of PET just prior to delivery. Maternal glycaemic control improved significantly prior to conception (P = 0.002) and remained euglycaemic (reflected by daily glucose profile, HbA1C and fructosamine) throughout gestation. Perinatal outcome was excellent. CONCLUSION: Captopril treatment before pregnancy has a prolonged protective effect on maternal renal functions during pregnancy and results in a favourable maternal-fetal outcome.