The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme: a randomized placebo-controlled trial

BACKGROUND: The role of intravenous (IV) albumin administration in the prevention of ovarian hyperstimulation syndrome (OHSS) and in the improvement of IVF conception outcomes was evaluated in a prospective, randomized, placebo-controlled double blind study. METHODS: Ninety-eight women were enrolled in the study and were consecutively assigned to either a treatment group or a control group. Eleven patients were lost to follow-up after assignment. Of the remaining 87 women, 46 received albumin on the day of oocyte retrieval, and 41 received 0.9% sodium chloride solution as a placebo control. Outcome measures included OHSS incidence rates and pregnancy rates in the two trial groups. RESULTS: Four of the 46 patients in the study group developed severe OHSS and six developed moderate OHSS. In the control group, one of the 41 developed severe OHSS and five developed moderate OHSS. The difference in OHSS incidence rates between the two groups was not statistically significant [relative risk (RR) = 1.49, 95% CI = 0.59-3.73]. Fourteen patients (30%) in the intervention group conceived, compared with 16 patients (39%) in the control group. The difference in conception rates between the two groups was not statistically significant (RR = 0.78, 95% CI = 0.44-1.39). CONCLUSIONS: Albumin appears to have no positive effect on OHSS or conception rates, while its use carries the risk of undesirable side effects, including exacerbation of ascites in OHSS, nausea, vomiting, febrile reaction, allergic reaction, anaphylactic shock and risk of virus and prion transmission. We suggest that this form of treatment should not be included in the prevention of OHSS.     

The use of metformin for women with PCOS undergoing IVF treatment

BACKGROUND: Metformin appears to improve reproductive function in some women with polycystic ovary syndrome (PCOS). We wished to explore the effect of metformin in women with PCOS undergoing IVF. METHODS: A randomized, placebo-controlled, double-blind study was carried out between 2001 and 2004. Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were randomized to receive metformin (MET), 850 mg, or placebo (PLA) tablets twice daily from the start of the down-regulation process until the day of oocyte collection. The primary outcome was to be an improvement in the overall fertilization rate. RESULTS: One-hundred and one IVF/ICSI cycles were randomized to receive metformin (52) or to receive placebo (49). There was no difference in the total dose of rFSH required per cycle (median dose: MET = 1200 U, PLA = 1300 U; P = 0.937). The median number of oocytes retrieved per cycle (MET = 17.2, PLA = 16.2; P = 0.459) and the overall fertilization rates (MET = 52.9%, PLA = 54.9%; P = 0.641) did not differ. However, both the clinical pregnancy rates beyond 12 weeks gestation per cycle (MET = 38.5%, PLA = 16.3%; P = 0.023) and per embryo transfer (MET = 44.4%, PLA = 19.1%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) was observed (MET = 3.8%, PLA = 20.4%; P = 0.023), and this was still significant after adjustment for BMI, total rFSH dose and age (OR = 0.15; 95% CI: 0.03, 0.76; P = 0.022). CONCLUSION: Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS.     

Complications of IVF and ovulation induction

BACKGROUND: The frequency and importance of complications of IVF and other ovulation induction (OI) are poorly known. We examined the occurrence of serious complications and miscarriages leading to hospitalization or operation after IVF (including microinjections and frozen embryo transfers) and OI treatment (with or without insemination). METHODS: Women who received IVF (n = 9175) or OI treatment (n = 10 254) 1996-1998 in Finland were followed by a register linkage study until 2000. RESULTS: After the first IVF treatment cycle, 14 per 1000 women had a serious case of OHSS (ovarian hyperstimulation syndrome), with 23 per 1000 throughout the study period (mean of 3.3 treatments). The corresponding values after OI were very low. The rates of registered ectopic pregnancies and miscarriages after IVF were nine and 42 respectively per 1000 women, with corresponding rates after OI of eight and 42. Infections and bleeding were not common after IVF and even rarer after OI. Overall, 15% of IVF and 8% of OI women had at least one hospital episode during the study period. CONCLUSIONS: Though there was a low risk of complications after each IVF treatment cycle, repeated attempts resulted in serious complications for many women, and these occurred much more often than after ovulation induction alone.     

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.     

First trimester bleeding in clinical IVF pregnancies

First trimester bleeding has been investigated in 72 pregnantwomen undergoing in-vitro fertilization and embryo transferand was compared to 70 pregnant patients in whom ovula tionwas induced, in addition to 70 spontaneous pregnancies. Abortionrates did not differ significantly between the first two groupsbut were significantly higher in comparison to normal pregnancies.Furthermore, among IVF pregnancies that continued, a high incidenceof first trimester bleeding occurred (P < 0.01). This complicationwas mainly related to luteal insufficiency and multiple pregnancies,whereas hyperstimulation was the major risk factor for bleedingin pregnancies arising from HMG-induced ovulation. Other currentlyunknown, aetiological factors for first trimester bleeding inIVF pregnancies remain to be investigated.     

Preventive attitude of physicians to avoid OHSS in IVF patients.

The ovarian hyperstimulation syndrome (OHSS) is a dramatic iatrogenic complication of fertility treatment. There is no consensus about its prevention strategies. We assessed whether physicians modify their preventive attitude in relation to clinical risk factors and to the oestradiol response chart. Three case scenarios with three levels of risk factors for OHSS were constructed. For each case scenario, four different charts of the oestradiol curve were described (peak serum oestradiol of 3590 or 6590 pg/ml obtained after a shorter or longer period). At random, we sent three out of the 12 artificially constructed case scenarios to 573 physicians who are members of the European Society of Human Reproduction and Embryology (ESHRE). They were asked whether they would cancel the cycle, take preventive measures or proceed to a regular IVF. A total of 389 cases from 130 different physicians was analysed. Globally, in 23% of the cases the physicians would proceed to a regular IVF. This decision varied significantly according to the risk level (between 38% in low risk to 8% in high risk cases; P < 0.01) and in relation to the oestradiol curve (P < 0.01). In 11% of the cases they would cancel the cycle and in 66% take some preventive measures. Among the selected preventive measures, coasting was by far the most popular choice (60%), followed by the use of i.v. albumin or hydroxyaethyl starch solution (36%) and cryo-preservation of all embryos (33%). In view of the sparse data as to whether coasting is really an effective method, and on how it should be carried out, we suggest that there is an urgent need to evaluate coasting as a preventive method in a large randomized trial in order to properly assess its efficiency and to provide precise guidelines for its use.     

A randomized study comparing IVF in the unstimulated cycle with IVF following clomiphene citrate

The efficiency of IVF in unstimulated cycles was compared with that following ovarian stimulation with clomiphene citrate in a simple protocol with ultrasound monitoring only. A total of 132 couples with no previous IVF attempts, selected by female age <35 years, indication for intracytoplasmic sperm injection or infertility caused by tubal factor or unexplained infertility were randomized to the two protocols. Randomization yielded two comparable groups. The clomiphene group (68 couples) performed significantly better than the unstimulated group (64 couples) in terms of number of cycles with oocyte harvest (90/111 or 81% versus 65/114 or 57%; chi(2) = 9.21, P < 0.002), embryo transfers per started cycle (59/111 or 53% versus 29/114 or 25%; chi(2) = 18.14, P < 0.0001), live intrauterine pregnancy rate per started cycle (20/111 or 18% versus 4/114 or 4%; chi(2) = 12.42, P < 0.0001), live intrauterine pregnancy rate per embryo transfer (20/59 or 34% versus 4/29 or 14%; chi(2) = 3.96, P = 0.047), but not in terms of implantation rate (22/85 or 26% versus 4/29 or 14%; chi(2) = 1.65). Only two twin pregnancies occurred. Modest side-effects were recorded following clomiphene. Accordingly, a simple clomiphene citrate protocol, but not IVF in unstimulated cycles, seems compatible with the concept of 'friendly IVF', yielding a fair pregnancy rate both per cycle started and per embryo transfer in selected patients. The results do not substantiate any important negative anti-oestrogenic effects of clomiphene.     

Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF

BACKGROUND: Only 25% of IVF transfer cycles lead to a clinical pregnancy, calling for continued technical progress but also more in depth analysis of patients' individual characteristics. The interleukin-1 (IL-1) system and matrix metalloproteinases (MMPs) are strongly implicated in embryo implantation. The genes coding for IL-1Ra (gene symbol IL-1RN), IL-1beta, MMP2 and MMP9 bear functional polymorphisms. We analysed the maternal genetic profile at these polymorphic sites in IVF patients, to determine possible correlations with IVF outcome. METHODS: One hundred and sixty women undergoing an IVF cycle were enrolled and a buccal smear was obtained. The presence of IL-1RN variable number of tandem repeats and IL-1B + 3953, MMP2-1306 and MMP9-1562 single nucleotide substitutions were determined. Patients were divided into pregnancy failures (119), biochemical pregnancies (8) and clinical pregnancies (33). RESULTS: There was a 40% decrease in IL-1RN*2 allele frequency (P = 0.024) and a 45% decrease in IL-1RN*2 carrier status in the clinical pregnancy group as compared to the pregnancy failure group (P = 0.017). This decrease was still statistically significant after a multivariate logistic regression analysis. The likelihood of a clinical pregnancy was decreased accordingly in IL-1RN*2 carriers: odds ratio = 0.349, 95% confidence interval = 0.2-0.8, P = 0.017. The IL-1B, MMP2 and MMP9 polymorphisms showed no correlation with IVF outcome. CONCLUSIONS: IL-1RN*2 allele carriage is associated with a poor prognosis of achieving a pregnancy after IVF.     

The effect of dydrogesterone supplementation in an IVF programme

Various treatments are given during the luteal phase by mostIVF programmes, without any proof of their efficacy. We haveperformed a double-blind, randomized study with dydrogesterone(125 transfers) against placebo (133 transfers). The pregnancyrate was 21.6 versus 15.0% per transfer cycle with dydrogesteroneor placebo, respectively. There was no significant differencebetween these figures, but taking into account the usual successrate in IVF programmes (15–20%) a difference of 5% wouldbe significant only with two groups of 1500 subjects. This paperdiscusses the question of how we can come to a definite conclusionon the efficacy of hormonal supplementation during the lutealphase.     

Tubal curettage: a new conservative treatment for haemorrhagic interstitial pregnancies

Haemorrhagic interstitial pregnancies are commonly treated by cornual resection. This invasive procedure may increase the risk of uterine rupture in subsequent pregnancies. We report here a case of a haemorrhagic interstitial pregnancy, associated with a viable intrauterine pregnancy in a salpingectomized woman, which was treated successfully by curettage of the uterine cornu.     

The use of fibrin sealant for embryo transfer: development and clinical studies.

Many embryo transfers after in-vitro fertilization may fail because of expulsion of the embryos from the uterus. Approximately 5-8% of pregnancies resulting from embryo transfer are ectopic. The aim of our study was to find a technique to avoid ectopic pregnancies and to improve the pregnancy rate. We used a two-component fibrin sealant which also contains a fibrinolysis inhibitor (aprotinin) at various concentrations. After gaining experience with mouse embryos, the sealant was used in human embryo transfer with great success. The results of a pilot study encouraged us to perform a prospective randomized study on 546 patients (270 with fibrin sealant, 276 conventional embryo transfers). There were 47 (17.0%) orthotopic pregnancies and 6 (2.2%) ectopic pregnancies in the control group, whereas there were 51 (18.9%) intrauterine and no ectopic pregnancies in the treatment group. The difference in ectopic pregnancies was statistically significant (P less than 0.05). With regard to the aprotinin concentration, there was a trend towards better results with 100-150 kIU (28.5% clinical pregnancies) in comparison to 250-300 kIU (19.2%) or no aprotinin (20.4%) (not significant). Further improvements of the technique may raise the pregnancy rate when fibrin sealant is used. As shown in our prospective randomized study, ectopic pregnancies may be completely avoided.     

Mortality in a cohort of IVF patients.

BACKGROUND: Risks associated with IVF and related assisted reproduction technologies include complications of ovarian stimulation, surgical procedures and pregnancy itself. Serious complications are uncommon but may be potentially life threatening. The aims of this study were to compare the mortality rates of women who received IVF treatment, as well as those who were referred but were not treated, with the mortality rate in the general female population, to determine the maternal mortality rate following IVF conception and to establish whether any deaths had occurred as a result of treatment complications. METHODS: Deaths were identified in a cohort of 29 700 Australian IVF patients by record-linkage with the National Death Index and a cancer registry. RESULTS: The all-cause mortality rates in IVF patients (treated and untreated) were significantly lower than in the general female population of the same age. In treated women, 72 deaths were observed and 125 deaths were expected giving an age-standardized mortality ratio of 0.58 (95% confidence interval 0.48-0.69). Two maternal deaths were identified in the 42 days of the puerperium. Complications of ovarian hyperstimulation syndrome could not be directly related to any of the deaths identified in this cohort. CONCLUSIONS: As well as providing some reassurance about the safety of IVF treatments, the findings point to the existence of a 'healthy patient effect' whereby the unhealthiest women in the population are deterred from pregnancy and infertility treatment.     

Are there predictive criteria of complicated ovarian hyperstimulation in IVF?

Among 599 trials of in-vitro fertilization (IVF) treatment, complicated ovarian hyperstimulation (OHSS) was diagnosed in 14 cases (2.5%) on the basis of heavy abdominal discomfort and echographic findings (ascites, ovarian enlargement with cysts). Among eight hospitalized patients, four presented with a haemoconcentration and/or electrolytic disturbances. OHSS cases were compared with two control groups for a series of criteria: age, aetiology of infertility, total dose of human menopausal gonadotrophin (HMG), day of oocyte collection, oestradiol (E2) peak level, rate of E2 increase, number of oocytes, number of embryos transferred and embryonic vitality scores. Comparison with a random group of normal IVF trials showed a significant difference for the following parameters: E2 peak level and rate of increase, E2/dose of HMG, E2/day of egg collection and number of oocytes. When OHSS cases were compared to another control group consisting only of high E2 responders (peak E2 greater than 2700 pg/ml), no significant difference was found for any of the above-mentioned criteria. In view of this lack of predictive power of individual criteria, stepwise discriminant analysis was applied, showing that this method might provide a predictive mathematical function for evaluating the risk of OHSS before human chorionic gonadotrophin (HCG) administration. Such a formula, however, should be validated by a multicentric study in which a greater number of OHSS cases would be tested.     

Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study

BACKGROUND: Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome (PCOS) scheduled for IVF stimulation. METHODS: Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria: hyperandrogenaemia, elevated LH/FSH ratio, hyperinsulinism, decreased SHBG levels or hirsutism, were studied. Normal weight and overweight patients were randomized separately in a prospective, randomized, double blind study. All patients were treated for at least 16 weeks with metformin (1000 mg bid) or placebo ending on the day of HCG injection. RESULTS: No differences were found in the primary end-points: duration of FSH stimulation 14.4 (13.1-15.7) versus 14.2 (12.6-15.7) days or estradiol on the day of HCG injection 6.8 (5.3-8.2) versus 7.6 (5.6-9.6) nmol/l in the metformin and placebo groups, respectively. The secondary end-points number of oocytes, fertilization rates, embryo quality, pregnancy rates and clinical pregnancy rates were equal. However, in the normal weight subgroup (BMI <28 kg/m(2), n = 27), pregnancy rates following IVF were 0.71 (0.63-0.79) versus 0.23 (0.15-0.31) in the metformin and placebo groups, respectively (P = 0.04). Overall clinical pregnancy rates were equal: 0.51 (0.34-0.68) versus 0.44 (0.27-0.62) in the metformin and placebo groups, respectively. However, in the normal weight subgroup, clinical pregnancy rates were 0.67 (0.43-0.91) and 0.33 (0.06-0.60), respectively (P = 0.06). CONCLUSIONS: Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome. However, among normal weight PCOS women, pre-treatment with metformin tends to improve pregnancy rates. Further studies in subgroups of PCOS women are required.     

Risk of benign gynaecological diseases and hormonal disorders according to responsiveness to ovarian stimulation in IVF: a follow-up study of 8714 women

BACKGROUND: Over the past decade, attention has been focused increasingly on the long-term health effects of IVF in women. Assuming that hormonal changes due to stimulation regimens for IVF are strongest among 'high' responders, we evaluated whether responsiveness to ovarian stimulation in IVF is predictive of the risk of benign gynaecological disorders >12 months after the last IVF cycle. METHODS: A nationwide historical cohort study of women who underwent IVF treatment was conducted. After a median time of 4.6 years following the last IVF treatment cycle, 8714 cohort members completed a health survey questionnaire that inquired about reproductive variables and the occurrence and age at onset of specific medical conditions including uterine leiomyoma, surgically removed ovarian cysts and thyroid disorders. Detailed data on cause of subfertility and IVF treatment were collected from the medical records. Women were included in the 'high responders' group when on average >/=14 oocytes were retrieved per IVF cycle (n = 1562), in the 'normal responders' group when they had a mean number of 4-13 retrieved oocytes (n = 6033), and in the 'low responders' group when they had a mean number of 0-3 retrieved oocytes per cycle (n = 1119). RESULTS: Among women with a high response to ovarian stimulation, we found a borderline significantly decreased risk of uterine leiomyoma [relative risk (RR) = 0.6; 95% confidence interval (CI) 0.4-1.0] and surgically removed ovarian cysts (RR = 0.6; 95% CI 0.3-1.0) in comparison with 'normal responders'. After OHSS, the age-adjusted RRs were 1.8 (95% CI 0.9-3.8) for having surgically removed ovarian cysts and 1.0 (95% CI 0.4-2.2) for uterine leiomyoma (both not significant). CONCLUSIONS: Despite the small number of events observed, highly elevated risks of gynaecological disorders and hormonal diseases in women undergoing IVF treatment can be excluded based on the present data and this follow-up period. Women with a low response to ovarian stimulation tended to have higher risks of benign gynaecological diseases than high responders.     

Chromosome studies in oocytes and zygotes from an IVF programme

Chromosome studies have been carried out in 117 oocytes, 17one-cell zygotes and four, two- to four-cell zygotes in ourIVF programme. Three apparently unfertilized oocytes were, infact, diploid zygotes. Two of 14 apparently polyspermic zygoteswere also diploid. One zygote with four pronuclei was pentaploid.This indicates that pronuclei can either be confused with othercytoplasmic structures, like vacuoles, or be eliminated. Endoreduplkationwas observed in one tetraploid, apparently polyspermic zygote,and in one two-cell degenerated zygote. The incidence of aneuploidyin unfertilized oocytes, taken as twice the level of hyperhaploidy,was 15.47percnt;. Five oocytes showed fragmented metaphase IIchromosomes (4.3%). The incidence of unreduced oocytes, dueto a lack of extrusion of the first polar body, was 6.87percnt;.Thus the total number of potentially aneuploid, polyploid ornon-viable zygotes due to chromosome aberrations in the oocytewas 26.5%     

The dilemma of the optimal surgical procedure in ectopic pregnancies occurring in in-vitro fertilization.

Ectopic pregnancy remains one of the undesired sequelae of in-vitro fertilization (IVF) treatment. It seems that mechanical infertility increases the risk of this complication in IVF. Thus, the surgeon treating such a case faces the dilemma of the optimal surgical procedure because of the increased risk for repeated ectopic pregnancy in subsequent IVF cycles. Two cases are presented with repeated ectopic pregnancy occurring in IVF. One case underwent salpingectomy on the first occasion and eventually developed a contralateral repeat ectopic gestation ending with salpingectomy. The second case underwent a conservative salpingotomy in the first event and developed a repeated ectopic gestation on the same side, undergoing bilateral salpingectomy. In order to prevent repeated ectopic pregnancies in an IVF programme, a definitive surgical procedure, such as bilateral salpingectomy, should be considered in the first episode in patients referred for IVF because of tubal pathology.     

Utilization of GnRH agonists for poor responders in an IVF programme

Thirty-four patients in whom conventional ovarian stimulation had previously failed twice due to low levels of oestradiol, received ovarian stimulation by pure FSH for 5 days, followed by a combination of FSH and HMG, after a preliminary period of pituitary de-sensitization with LHRH agonist. Oocytes were recovered from 33 patients and 28 embryos replaced, 10 became pregnant and eight pregnancies were ongoing and resulted in the birth of 13 healthy babies. This ongoing pregnancy rate of 23.5% per treatment cycle is identical to that reported for normally responding patients. The use of LHRH agonists in so-called poor responders is of obvious interest.     

Comparison of a fixed and dynamic protocol for embryo replacement in an IVF/ET programme

Implantation after embryo transfer is considered a major obstadein terms of pregnancy rates after in-vitro fertilization. Aflexible approach to the date of replacement, based on the factthat the most suitable embryonic structure for proper implantationis the four- to eight-cell embryo, has been studied. One-hundred-and-twentypatients with various aetiologies of infertility were stimulatedwith HMG or combined HMG and FSH, then treated by three differentmethods of embryo replacement. In group I embryos were replacedin mothers 48 h after ovum retrieval; in group II replacementswere carried out 72 h after retrieval; and in group III replacementswere related to embryonic cleavage development. Mean levelsof oestradiol when HCG was given averaged 1301 ± 121pg/ml, 1016 ± 96 pg/ml and 1182 ± 101 pg/ml inthe three groups, respectively. There was no significant differencein the average number of embryos transferred among the variousgroups. The pregnancy rates per transfer were 21.8, 24.2 and38.7%, respectively (P < 0.001). Although more investigationis required, a dynamic approach to embryo replacement mightsignificantly improve pregnancy rates, because of improved interactionsbetween the embryos and the uterus.     

Influence of position and length of uterus on implantation and clinical pregnancy rates in IVF and embryo transfer treatment cycles

In a prospective study of 807 consecutive women shown to have an apparently normal uterus after hysterosalpingography, hysteroscopy or pelvic ultrasonography prior to IVF or intracytoplasmic sperm injection (ICSI) and embryo transfer, the position and length of the uterine cavity was measured routinely at a pre-treatment mock transfer procedure. The apparent length of the uterine cavity was <7 cm in 128 women (group 1), 7-9 cm in 594 women (group 2) and >9 cm in 85 women (group 3). The uterus was noted to be retroverted in 38. 2% (308) women. The embryo transfer catheter was advanced to 5 mm from the uterine fundus based on the previously determined cavity length in all the embryo transfer procedures at 48 h after oocyte collection. Implantation and clinical pregnancy rates were not significantly different with respect to position of the uterus, difficulties encountered in passage of the catheter, mean age of the women, aetiology or duration of infertility or embryology events. An apparently greater cavity length was seen in older and/or parous women, but the difference was not statistically significant. Although the highest implantation and clinical pregnancy rates were seen in women with a cavity length of 7-9 cm (group 2) the differences were not statistically significant: group 1, 18.9 and 36. 7%; group 2, 21.0 and 46.5%; and group 3, 17.3 and 32.9% respectively. The incidence of ectopic pregnancy per reported clinical pregnancy was highest in group 1 women, being 14.9% (7/47) in comparison with group 2 (1.8%, 5/276) and group 3 (0%, 0/27) (P: < 0.0005), suggesting that the size of the uterus is a critical factor in the aetiology of ectopic pregnancy in IVF/ICSI-embryo transfer.