Increased early pregnancy loss in IVF patients with severe ovarian hyperstimulation syndrome.

BACKGROUND: Since severe ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of assisted reproduction, the focus of attention in such cases is placed firmly upon the health of the patient, with the endeavour to achieve a pregnancy being considered of secondary importance. The aim of this study was to focus on the pregnancy rate and pregnancy outcome in IVF patients hospitalized for severe or critical OHSS, in one centre, during a period of 6 years. METHODS: We compared the characteristics of patients with severe OHSS: those who conceived with the ones who did not conceive, and among pregnant IVF patients, those with ongoing pregnancies with those that miscarried. RESULTS: Pregnancy was achieved in 60 of 104 (58%) patients with severe OHSS. Pregnancy continued until delivery in 37 of these 60 patients (62%), whereas the remaining 23 (38%) aborted. The pregnancy and abortion rates in patients with severe OHSS were significantly higher than those of IVF patients without OHSS, during the same time period [23% (1138/4922) and 15% (169/1138) respectively, P < 0.001]. The mean duration of hospitalization for OHSS was significantly shorter in those who delivered compared with those who aborted (5.9 +/- 3.2 versus 10.5 +/- 9.6 days, P < 0.01) and in the non-pregnant patients compared with the pregnant patients (5.2 +/- 3.2 versus 7.6 +/- 6.6 days, P < 0.02). CONCLUSIONS: The clinical pregnancy rate of IVF patients with severe OHSS was significantly higher than that of patients without the syndrome. A longer stay in hospital-reflecting a more severe form of OHSS-was correlated with a higher frequency of abortions. OHSS, necessitating hospitalization, is a detrimental clinical situation not only for the mother but also for the developing pregnancy.     

Evaluation of variations in pregnancy rates, implantation rates and early abortion rates within an in-vitro fertilization programme

Despite the application at this clinic of a standardized programmefor in-vitro fertilization of human oocytes over the last 27months, great variations in the rates of implantation, clinicalpregnancy and early abortion have been observed during certainperiods. A retrospective evaluation of these results showedthat these variations occurred in periods when various commerciallyavailable batches of Earle‘s medium (the medium was theonly variable changed during the 27 months) were used and thattwo sub-optimal batches of Earle’s medium from one ofthe sources used during one of three periods (period 2) wasmost likely to be responsible for sub-optimal embryo qualityand, consequently, for a halving of the pregnancy rate (30 versus15%) and of the implantation rate (11 versus 5%) and an increasein the early abortion rate (23 versus 50%), It is concludedthat the quality of the culture medium is of major importancefor the success of an IVF programme. The factor(s) in the mediumresponsible for the decrease in embryo quality has not beenidentified.     

Incidence and significance of unequal gestational sac diameter or embryo crown-rump length in twin pregnancy.

The incidence of differences in gestational sac diameter and crown-rump length, measured at the time of the first ultrasound, in which at least one gestational sac or crown-rump length could be visualized, were analysed retrospectively in 260 twin pregnancies in which one or both fetuses were delivered at term. The difference in gestational sac diameter averaged 1.2 +/- 0.1 mm for pregnancies which ended in twin births, compared to 2.0 +/- 0.3 mm when pregnancy ended in single births (P less than 0.02). The difference in crown-rump length averaged 2.4 +/- 0.6 mm for pregnancies which ended in a single birth, compared to 0.9 +/- 0.1 mm for twin births (P = 0.02). Disparities of greater than or equal to 3 mm in gestational sac diameter (P less than 0.05) or crown-rump length (P less than 0.001) were associated with an embryo loss rate greater than or equal to 50%. The disparity in gestational sac diameter (P less than 0.04) and crown-rump length (P less than 0.01) was smaller in pregnancies resulting from assisted reproductive technologies, compared with pregnancies resulting from coitus or insemination. Differences in gestational sac diameter and crown-rump length in early pregnancy were unrelated to differences in birth weight, length or sex.     

A family history of twinning in relation to multiple implantation

BACKGROUND: A familial basis for dizygotic twinning is known for multipleovulation. However, for multiple implantation this remains unclear.In IVF/intracytoplasmic sperm injection (ICSI) ‘multipleovulation’ is artificially induced. If multiple implantationis not hereditary, the incidences of twins in families of patientswith single and multiple implantation after IVF/ICSI with doubleembryo transfer (DET) should be comparable. METHODS: A questionnaire study was conducted among patients with intrauterine pregnancy at 6 weeks of gestation, after IVF/ICSI treatmentwith DET 3 days after oocyte retrieval. RESULTS: There were 940 patients who gave their informed consent. Forwomen with single implantation (Group A), the incidence of oneand of multiple twins among the family was 27.2 and 15.5%, respectively.For women with multiple implantation (Group B), this incidencewas 29.5 and 17.8%, respectively, P = 0.424. The incidence ofone and of multiple twins among first degree relatives was 10.6and 1.1% in Group A; for Group B this was 8.7 and 1.9%, P =0.469. Multivariate regression analysis also did not reveal‘twins in family’ or ‘twins in first degree’as an associated variable for multiple implantation at 6 weeks. CONCLUSIONS: Incidences of twins in families of patients with single implantationand patients with multiple implantation after IVF/ICSI are comparable.Our data do not support the concept that multiple implantationis hereditary.     

Maternal homocysteine and chorionic vascularization in recurrent early pregnancy loss

Defective chorionic villous vascularization has been suggested to be associated with embryonic death. There are no reports, however, describing chorionic vascular profiles in spontaneous miscarriage tissue. Therefore, we investigated chorionic villous vascularization by both histopathology and an image analysis system combined with CD34 immunohistochemistry in spontaneous miscarriage tissue of 19 women with recurrent early pregnancy loss (REPL). Subsequently, we studied the vascular profile parameters (median vascular area, perimeter, number of vascular elements per measured chorionic area, and the median area, perimeter and diameter per vascular element) in relation to the maternal plasma total homocysteine concentrations (an independent risk factor for REPL). The histopathological scores and the measured number of vascular elements per mm(2) chorionic tissue were not significantly different between women with elevated and those with normal total homocysteine concentrations. However, women with elevated total homocysteine concentrations (fasting >18.3 micromol/l and/or 6 h after methionine load >61.5 micromol/l) showed (per measured chorionic area) significant smaller median vascular areas and perimeters. The single chorionic vascular elements in these women had significant smaller median areas, perimeters and diameters. Furthermore, the fasting total homocysteine was negatively correlated with the perimeter of the vascular element (r = -0.54: P <0.05). In conclusion, in REPL, elevated maternal total homocysteine concentrations are associated with defective chorionic villous vascularization.     

The influence of inadvertent intranasal buserelin administration in early pregnancy

Buserelin was inadvertently administered during 13 early pregnancies in 12 women with long-standing infertility, who had started the GnRH-agonist for gonadotrophin desensitization prior to ovarian stimulation for IVF. Six women delivered a healthy child and one pregnancy continues uneventfully. Three patients aborted before the sixth week and three women with tubal disease had an ectopic pregnancy. Corpus luteum function was normal in 11 of the 13 pregnancies. Although no evidence of embryotoxic effects of buserelin was observed, barrier contraceptive methods should be advised during the first days of its administration.     

Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: a prospective randomized clinical trial.

A prospective randomized study comparing single embryo transfer with double embryo transfer after in-vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) was carried out. First, top quality embryo characteristics were delineated by retrospectively analysing embryos resulting in ongoing twins after double embryo transfer. A top quality embryo was characterized by the presence of 4 or 5 blastomeres at day 2 and at least 7 blastomeres on day 3 after insemination, the absence of multinucleated blastomeres and <20% cellular fragments on day 2 and day 3 after fertilization. Using these criteria, a prospective study was conducted in women <34 years of age, who started their first IVF/ICSI cycle. Of 194 eligible patients, 110 agreed to participate of whom 53 produced at least two top quality embryos and were prospectively randomized. In all, 26 single embryo transfers resulted in 17 conceptions, 14 clinical and 10 ongoing pregnancies [implantation rate (IR) = 42.3%; ongoing pregnancy rate (OPR) = 38.5%] with one monozygotic twin; 27 double embryo transfers resulted in 20 ongoing conceptions with six (30%) twins (IR = 48.1%; OPR = 74%). We conclude that by using single embryo transfer and strict embryo criteria, an OPR similar to that in normal fertile couples can be achieved after IVF/ICSI, while limiting the dizygotic twin pregnancy rate to its natural incidence of <1% of all ongoing pregnancies.     

Placental protein 14 in human in-vitro fertilization early pregnancies.

Placental protein 14 (PP14) and human chorionic gonadotrophin (HCG) were analysed in patients participating in an in-vitro fertilization-embryo transfer programme which did not include any kind of luteal support. Women with normal pregnancies, spontaneous abortions, ectopic pregnancies, biochemical pregnancies and non-pregnant women were compared. A combination of HCG and PP14 analyses distinguished between normal and abnormal implantation as early as 15 days after oocyte retrieval. The product of HCG (IU/l) and PP14 (micrograms/l) concentrations differed significantly between normal pregnancy, spontaneous abortion and ectopic pregnancy (P = 0.0248). It is concluded that both endometrial (PP14) and trophoblastic (HCG) markers, when used in combination, exhibit changes in abnormal implantation which may be clinically useful.     

Lack of seasonal variations in fertilization, pregnancy and implantation rates in women undergoing IVF

BACKGROUND: Several studies have investigated seasonal variations during IVF. Their results are contradictory, especially concerning fertilization and pregnancy rates. The aim of the present study was to re-evaluate these parameters using a large number of IVF cycles. METHODS: A total of 7368 IVF cycles conducted in Switzerland between 1995 and 2003 were retrospectively analysed. To avoid a bias in the evaluation of the fertilization rate, only IVF cycles without ICSI were considered for analysis. Cycles were assigned to seasons according to the date of the beginning of stimulation. RESULTS: There were no statistically significant differences between the seasons concerning the fertilization, the pregnancy and the implantation rates. However, statistically significant variables deciding on the outcome of an IVF cycle are age, centre, aetiology of infertility and day of transfer. CONCLUSIONS: There were no statistically significant seasonal differences in central Europe (Switzerland) that influenced the outcome of IVF treatment. The only statistically significant variables of IVF outcome were age, centre, aetiology of infertility and day of transfer. A change to routine fertility treatment concerning the different seasons should therefore not be taken into account.     

Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF

BACKGROUND: We aimed to study T-helper 1 (Th1) and Th2 intracellular cytokine expression in peripheral blood lymphocytes of women with recurrent spontaneous abortions (RSA) or infertility with multiple implantation failures after IVF cycles. METHODS: Twenty-six women with three or more RSA and 23 with two or more IVF failures (14 with no history of spontaneous abortion (SAB) and nine with more than one SAB) comprised the two study groups. Twenty-one non-pregnant healthy multiparous women served as controls. Proportions (%) of lymphocytes containing IFN-gamma, TNF-alpha, IL-4 and IL-10 and the Th1/Th2 ratios of IFN-gamma/IL-4, IFN-gamma/IL-10, TNF-alpha/IL-4 and TNF-alpha/IL-10 in CD3+, CD3+/CD8- (T helper) and CD3+/CD8+ (T suppressor) cells were measured by 4-colour flow cytometry. RESULTS: RSA women demonstrated significantly higher Th1/Th2 ratios of IFN-gamma/IL-4 (P < 0.01), TNF-alpha/IL-4 and TNF-alpha/IL-10 (P < 0.05 each) in CD3+/CD8- T helper cells than those of controls. The proportion of TNF-alpha producing CD3+/CD8- cells (P < 0.05), and the Th1/Th2 ratios of TNF-alpha/IL-4 (P < 0.05) and TNF-alpha/IL-10 (P < 0.005) in CD3+/CD8- cells were significantly higher in women with multiple IVF failures without SAB as compared with those of controls. CONCLUSIONS: The prevalence of dominant Th1 immune responses in peripheral blood lymphocytes may reflect the systemic contribution of Th1 cytokines to RSA or multiple implantation failures in IVF cycles.     

Reliability of serial urine HCG as a biomarker to detect early pregnancy loss

BACKGROUND: To examine the reliability of HCG as a biomarker for early pregnancy loss, five experienced researchers independently assessed data from 153 menstrual cycles, determining whether each cycle represented 'no conception,' a 'continuing conception' or a 'conception lost.' METHODS: Urine samples were analysed by immunoradiometric assay using a combination of capture antibodies for the intact heterodimer (B109) and for an epitope common to the beta subunit and the beta core fragment (B204). For each cycle, HCG data were presented as graphs of daily assay results. Summary statistics for HCG assays from 46 women who had undergone bilateral tubal ligation represented baseline values. RESULTS: Pairwise agreement among the assessors for any of the three options ranged from 78-89%. At least three experts agreed for 147 cycles (96%), accounting for 28 conception losses and 19 continuing conceptions. The multi-rater kappa was 0.62 for the conception lost category and 0.68 for continuing conceptions, indicating substantial agreement. CONCLUSION: The main sources of disagreement involved deciding whether there was sufficient information for assessment, interpreting cycle parameters such as cycle length or bleeding event, and interpreting a distinct HCG rise pattern that does not exceed the baseline value obtained from the sterilized women.     

Survival rates during the first trimester of multiple gestations achieved by ICSI: a report of 1448 consecutive multiples

BACKGROUND: The purpose of this study was to determine the rate of spontaneous gestational sac loss during the first trimester in women achieving multiple pregnancies by ICSI. METHODS: A retrospective analysis was performed of 1448 consecutive multiple pregnancies conceived by ICSI. RESULTS: Of the cohort of 1448 pregnancies, twin gestations constituted 59.6% (864), triplets 30.2% (438) and quadruplets 10.0% (146). During the first trimester, 69 (4.7%) patients miscarried, while 179 (12.3%) continued their pregnancies and had fewer gestational sacs at the end of the first trimester than at the beginning. The overall loss rate of any gestational sac during the first trimester in these multiple pregnancies was 10.1%. There was a significant difference in the frequency of spontaneous reduction to twin or singleton pregnancies in the first trimester between women carrying triplets (11.7%) and those carrying quadruplets (3.5%) [P = 0.004; odds ratio (OR) 3.5; 95% confidence interval (CI) 1.3-9.1]. The frequency of gestational sac loss was significantly greater among women >35 years old (20.9%) than in women less than 35 years old (15.9%) (P = 0.03; OR 1.4; 95% CI 1.0-1.9). CONCLUSION: In multiple pregnancies there is a significant risk of spontaneous loss of any embryo during the first trimester. These findings should be considered prior to any decision about selective embryo reduction.     

High serum oestradiol concentrations in fresh IVF cycles do not impair implantation and pregnancy rates in subsequent frozen-thawed embryo transfer cycles

High oestradiol concentrations may be detrimental to the success of in-vitro fertilization (IVF) treatment. A total of 1122 women aged <40 years who were undergoing their first IVF cycle were evaluated retrospectively. Serum oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration were categorized into three groups: group A <10 000 pmol/l; group B 10 000-20 000 pmol/l and group C >20 000 pmol/l. In fresh cycles, group A had significantly lower pregnancy rates per transfer (16.2 versus 23.7% respectively, P = 0.005, chi(2)) and implantation rates (8.7 versus 11.7% respectively, P = 0.037, chi(2)), when compared with group B. The pregnancy rate per transfer in group C was significantly lower than that in group B (12.1 versus 23.7%, P = 0.049, chi(2)) and group C had the lowest implantation rate (6.4%). In frozen-thawed embryo transfer cycles, implantation rates in groups A, B and C were similar (7.5, 8.1 and 9.6% respectively) and the pregnancy rates were also comparable in all groups. In conclusion, high serum oestradiol concentrations in fresh IVF cycles may adversely affect implantation and pregnancy rates. Embryo quality seemed unaffected as excess embryos from different groups had similar implantation and pregnancy rates in frozen-thawed embryo transfer cycles. The reduced implantation was probably due to an adverse endometrial environment resulting from high serum oestradiol concentrations.     

A prospective study of early pregnancy loss

The New York State Early Pregnancy Detection Study was a prospectivestudy of early pregnancy loss, between implantation and menses,in 217 women attempting to become pregnant during 1989–1992.Women collected urine samples on three consecutive morningsduring the late luteal phase of their menstrual cycle, for upto 12 cycles, contributing samples for 1253 menstrual cycles.Urinary human chorionic gonadotrophin (HCG), measured usingan immunoradiometric assay, was the biomarker for pregnancy.We observed a range of early pregnancy loss (EPL) rates, froma low estimate of 11.0% to a high estimate of 26.9%, dependingon the definition used and the subgroup analysed. Based on adefinition of 3 days of HCG concentration > 4.00 pmol/1,2 days 3=533 pmol/1 or the last, day of HCG 2 = 6.67 pmol/1,we identified 115 positive cycles; 95 cycles were clinicallyconfirmed pregnancies and 20 cycles were EPL, giving an EPLrate of 17.4% [95% confidence interval (CI) 11.0-25.6]. In addition,we observed an EPL rate of 19.5% (95% CI 113-30.1) for samplescollected within a 15 day window around menses, and a rate of203% (95% CI 113-32.2) for samples limited to the first threemenstrual cycles. Because studies use urine collection schemesother than daily sampling, the definition of pregnancy willbe crucial in defining EPL.     

Pregnancy: Oocyte donation in women with recurrent pregnancy loss

The prognosis of couples with recurrent miscarriage is controversialdespite efforts made during this century to learn about thephyslopathology and treatment of this troublesome condition.Here we present our experiences of employing oocyte donationin eight couples in whom the woman was a low responder to gonadotrophinstimulation and had a previous history of recurrent abortionwith negative routine infertility work-up for repeated pregnancyloss. Patients were desensitized with gonadotrophin-releas inghormone analogues and supplemented with oestradiol valeratefor a minimum of 15 days until oocytes were donated from in-vitrofertilization and fertile donors. Then, progesterone was addeduntil day 100 of pregnancy. A total of 12 oocyte donation cycleswere performed in these patients. Clinical pregnancy and deliveryrates per cycle were 75.0 and 66.6% respectively. The deliveryrate per patient was 85.7% in this series, and the miscarriagerate per cycle was 11.1%. The results of ovum donation comparedfavourably with low responders without a history of recurrentabortion undergoing this treatment during the study period.These results strongly suggest that the oocyte may be the originof infertility in women with idiopathic recurrent miscarriages.In addition, the results question the role of maternal localand systemic factors in early recurrent pregnancy loss, as wellas the paternal contribution to its aetiology.     

Exposure to LHRH agonists in early pregnancy following the commencement of mid-luteal buserelin for IVF stimulation.

Exposure to buserelin in early pregnancy has been reported following its use in in-vitro fertilization treatment cycles. The number of reported cases is small. There are still no answers regarding embryotoxicity, and the need for luteal support is still unclear. A further six cases are reported here, five receiving luteal support and resulting in the delivery of healthy children, and one, without luteal support ending in a first trimester miscarriage. We propose that further data should be collected to allow adequate monitoring and follow-up of these pregnancies.     

Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss

BACKGROUND: The genetic predispositions to venous thrombosis such as factor V Leiden (FVL) mutation (Arg 506 Gln), prothrombin (FII) gene mutation (G20210A), and mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) have been reported to be associated with recurrent pregnancy loss. This paper examines the prevalence of markers for genetic thrombophilias in women with recurrent miscarriage. METHODS: The prevalence of FVL, FII G20210A and MTHFR C677T was compared in 108 women with three or more pregnancy losses either exclusively in the first trimester, or mixed first and second trimester losses, with the prevalence found in 82 fertile parous control women without miscarriages. Markers for the thrombophilias were assessed by PCR analysis. RESULTS: Twenty-three of the 108 patients (21.3%), had thrombophilia markers, which was similar to the proportion of patients in the control group (20.7%) with these markers. The prevalences of FVL and FII G20210A were lower in the study group than in the control group (3.7 versus 6.1% for FVL and 4.6 versus 6.1% for FII respectively); however, the difference was not statistically significant. In contrast, the prevalence of MTHFR C677T was higher in the study group than the control population (13 versus 8.5% respectively), but this difference was not statistically significant. There was no statistically significant prevalence of any particular thrombophilia in patients with previous first and second trimester pregnancy losses compared with patients with first trimester losses alone. CONCLUSION: Thrombophilia was not found to be associated with recurrent pregnancy loss.     

Early pregnancy loss following assisted reproductive technology treatment

BACKGROUND: In women treated by assisted reproductive technology (ART), early pregnancy loss (EPL) reduces the initial success. Risk factors for EPL, however, have not been comprehensively studied. This study assesses some potential risk factors in ART pregnancies. METHODS: Altogether 1196 pregnancies, defined as serum hCG >or=10 IU/l on day 16 +/- 1 after oocyte retrieval, were included in this study. EPL was defined as pregnancy loss that occurred before 6-7 weeks gestation. Risk factors investigated were maternal age, body mass index (BMI), smoking and polycystic ovary syndrome (PCOS) status, infertility aetiology, response to stimulation, quality and number of embryos replaced and treatment type. RESULTS: Overall EPL was 16%. The risk of EPL was not linearly related to either age or BMI. Though women >40 years old had an increased risk, this was not significant after adjusting for other factors. The risk in both lean (BMI <18.5 kg/m(2)) and very obese (BMI >35 kg/m(2)) women was also not significantly higher in multivariate analysis. There was no effect of PCOS. Smoking or transfer of 'poor quality' embryo(s) was associated with a significant increased risk of EPL after adjusting for other factors. CONCLUSION: Smoking and transferring poor quality embryos increased EPL, while the effects of age, obesity and other risk factors were not significant in a multivariate analysis.     

Factors related to subsequent reproductive outcome in couples with repeated pregnancy loss

Specific factors in a couple's history may influence the recurrence risk following repeated pregnancy loss (RPL). Couples with RPL were contacted several years following evaluation and information concerning subsequent pregnancies was obtained. Linear regression analysis was utilized to determine which factors in the history were significant predictors of pregnancy outcome following evaluation. A family history of RPL or a “genetic defect” was a highly significant predictor of subsequent unsuccessful pregnancies. Surgical, but not medical, treatment for RPL was a significant predictor of eventual successful outcome. The number of abortions prior to evaluation for RPL, presence of a liveborn child, maternal age at evaluation, and intercurrent infertility all failed to be significant predictors of pregnancy outcome after evaluation.     

Conception to ongoing pregnancy: the 'black box' of early pregnancy loss

Even when conditions are optimal, the maximum chance of a clinically recognized pregnancy occurring in a given menstrual cycle is 30-40%. Increasing evidence points to preclinical pregnancy loss rather than failure of conception as the principal cause for the relatively low fecundity observed in humans. While sensitive assays for hCG have provided a glimpse of the events occurring between implantation and the missed menstrual period, new cytogenetic techniques have further opened this 'black box', providing novel insights into the causes of early pregnancy wastage. In this article, the evidence and causes of preclinical or 'occult' pregnancy are reviewed, and the implications for the infertile patient are addressed.