Multiple pregnancy after in-vitro fertilization and embryo transfer: report of a quadruplet pregnancy and delivery

The first baby from in-vitro fertilization (IVF) was born in England in 1978 as a result of retrieval of a single preovulatory oocyte in the course of a natural cycle (Steptoe and Edwards, 1978). At present most programmes of IVF throughout the world do not use natural cycles producing only one oocyte, but rather multiple oocyte cycles produced by clomiphene citrate (CC), human menopausal gonadotrophin (HMG), or pure follicle stimulating hormone (FSH), either separately or in combination, sequentially or concomitantly, for the induction of multiple follicular maturation.     

Comparison of two elective transfer policies of two embryos to reduce multiple pregnancies without impairing pregnancy rates.

A first elective transfer policy of two embryos based solely on embryo morphology was compared to a more restrictive policy transferring two embryos to all patients aged < 35 years with less than three previous cycles to reduce the incidence of multiple pregnancies. With a significant reduction in the number of triple transfers from 72.4 to 44.3%, the delivery rates were similar for both policies, 31 and 32.1%. However, the multiple pregnancy rates per transfer significantly decreased from 12.5 to 7.8% (P < 0.05). Of 99 pregnancies, only 24.2% were multiple including 1% of triplets compared to 40.7% multiple pregnancies including 6.7% of triplets for the first policy. Forty-eight transfers of two average embryos with the new policy were compared to 264 transfers of three average embryos with the old policy. Multiple pregnancy rates per transfer were significantly reduced by a third from 23 to 8% (P < 0.05) without a reduction of the pregnancy rates (42 and 48%). This study demonstrated that elective transfer of two embryos reduced the number of multiple pregnancies without impairing the pregnancy rates even with the transfer of average embryos.     

Broad ligament twin pregnancy following in-vitro fertilization

We report the first case of an ectopic twin pregnancy in the broad ligament following in-vitro fertilization and embryo transfer in a patient with a previous ipsilateral (left) salpingo-oophorectomy. The previous surgery was for endometriosis. We discuss the possible contribution of the embryo transfer technique, limitations of preventive measures and importance of transvaginal ultrasound in establishing the diagnosis.     

Infertility: Assessments of embryo transfer after in-vitro fertilization: effects of glyceryl trinitrate

The role of embryo transfer and its associated difficultieson the outcome of human in-vitro fertilization (IVF) were examinedusing a standardized procedure and a scoring system (embryotransfer scores 1–5). This system was used to assess anyeffects of the smooth muscle relaxant glyceryl trinitrate (GTN)on embryo transfer. Patients (n = 120) were randomized in adouble-blind manner at their first embryo transfer to receivesublingual GTN or placebo before the transfer. Retrospectiveanalysis showed that higher pregnancy rates were associatedwith uncomplicated transfers (score 1; P < 0.01). The outcomemeasures included pregnancy rate, total time of cervical manipulation(embryo transfer time) and embryo transfer score. All pregnancieshad a transfer score of 1 or 2, but no recorded parameter differentiatedbetween pregnant or non-pregnant cycles, and GTN had no significanteffect on any parameter.     

Case Report: Perforated appendicitis and ectopic pregnancy following in-vitro fertilization

This report describes a case of perforated appendicitis andectopic pregnancy following in-vitro fertilization (IVF) andembryo transfer. Perforated appendicitis was a coincidentalevent following IVF and embryo transfer. Immediate diagnosisand treatment of the perforated appendicitis saved the lifeof the patient. The ectopic pregnancy was completely resolvedwith two doses of methotrexate administration.     

Pregnancy: The prediction of ectopic pregnancy after in-vitro fertilization and embryo transfer

Data from 135 patients who suffered ectopic pregnancies andfrom 135 patients who progressed to singleton deliveries afterin-vitro fertilization and embryo transfer have been analysedretrospectively. The ectopic pregnancies represent all suchcases observed at Bourn Hall Clinic between 1983 and 1993. Thedelivered group was randomly selected from the same time period.The ectopic pregnancies included 20 heterotopic, eight ovarianand six bilateral tubal pregnancies; the remainder were singletontubal pregnancies. The aim of this study was to identify thevariables which differed systematically for the two groups ofpatients and to explore whether such variables could be usedto predict ectopic pregnancy at an early stage. The mean plasmaconcentration of human chorionic gonadotrophin and progesteronefor the ectopic pregnancy group was significantly lower thanthat for the singleton delivery group (P < 0.001). However,there was such a degree of overlap that it was impossible todevise a cut-off concentration for either hormone which wouldoffer a clinically useful predictor of ectopic pregnancy. Nevertheless,using the discriminant function analysis of these data, togetherwith the history of pelvic inflammatory disease, we could predictup to 90% of cases of ectopic pregnancy by day 23 after embryotransfer, long before ultrasound imaging would be useful.     

Pregnancy: Intramural pregnancy following difficult embryo transfer

We report an intramural pregnancy following a difficult embryotransfer in a 31 year-old woman, having in-vitro fertilizationand embryo transfer for tubal factor infertility. The creationof a ‘false passage’ at a previous instrumentationof the cervix may be implicated in the ectopic placement ofembryos     

Pregnancy: Endometrial ultrasonography as a predictor of pregnancy in an in-vitro fertilization programme

The endometrial pattern and thickness were analysed by ultrasonographyin 139 cycles stimulated for in-vitro fertilization (IVF) onthe day of administration of human chorionic gonadotrophin (HCG).A semi-programmed schedule based on the pill + clomiphene citrate+ human menopausal gonadotrophin (HMG) was used in all cycles.On the day of HCG administration, endometrial pattern and thicknesswere assessed with an Ultramark 4 (ATL) ultrasound equippedwith a 5 MHz vaginal probe. Endometrial pattern I (a ‘tripleline’multilayer) was observed in a total of 105 cycles (76%), andpattern II (fully homogeneous and hyperechogenic in relationto myometrial tissue) in 34 (24%). The incidence of clinicalpregnancy did not differ (P = 0.52) between the groups withendometrial patterns I (23.8%) and II (29.4%). Endometrial thicknesson the day of HCG administration in the group with pattern I(8.4 ± 1.9 mm) was similar (P = 0.96) to that observedin the group with pattern II (8.4 ± 2.0 mm). In addition,the endometrial thickness of the patients who became pregnant(8.0 ± 1.7 mm) did not differ (P = 0.15) from that ofwomen who did not achieve pregnancy (8.6 ± 2.0 mm). Theconclusion from the present data is that ultrasonographic analysisof endometrial thickness and refringency on the day of HCG administrationhad no predictive value for conception in IVF cycles.     

Reducing the number of embryos transferred in Sweden-impact on delivery and multiple birth rates

BACKGROUND: Reduction of the number of embryos transferred has been introduced to decrease the multiple birth rates (MBRs) after IVF and the associated risks for the children. The aim of this report is to present the effect of two steps in reduction of the number of embryos transferred, when applied in the majority of the patients, on national data for delivery and MBR after IVF in Sweden. METHODS: This observational study is based on annual reports from all IVF clinics in Sweden to the National Board of Health and Welfare for the time period 1991-2004. RESULTS: The main finding is that despite a successive reduction in the number of embryos transferred, delivery rates were maintained at around 26% while MBR decreased dramatically, from about 35% to around 5%. The same pattern was noticed, independent of age, for all women below 40. In comparison with the USA, lower delivery and MBR were noted for Sweden whereas a higher 'birth per embryo transferred' was found. CONCLUSIONS: Single embryo transfer (SET) results in satisfactory delivery rates and a dramatic decrease in the MBRs, also when applied on a broad scale. The experience from Sweden ought to encourage other countries to introduce SET more widely.     

A more realistic approach to the cumulative pregnancy rate after in-vitro fertilization

As most studies overestimate the cumulative pregnancy rate,a method is proposed to estimate a more realistic cumulativepregnancy rate by taking into account the reasons for an earlycessation of treatment with in-vitro fertilization (IVF). Threemethods for calculating cumulative pregnancy rates were compared.The first method assumed that those who stopped treatment hadno chance at all of pregnancy. The second method, the one usedmost often, assumed the same probability of pregnancy for thosewho stopped as for those who continued. The third method assumedthat only those who stopped treatment, because of a medicalindication, had no chance at all of pregnancy and that the otherswho stopped had the same probability of pregnancy as those whocontinued treatment Data were used from 616 women treated atthe University Hospital Nijmegen, Nijmegen, The Netherlands.The cumulative pregnancy rates after five initiated IVF cyclesfor the three calculation methods were in the ranges 37–51%for the positive pregnancy test result, 33–55% for a clinicalpregnancy and 30–56% for an ongoing pregnancy. As expected,the first method underestimated the cumulative pregnancy rateand the second overestimated it The third method produced themost realistic cumulative pregnancy rates.     

Pregnancy: Supraphysiological serum relaxin concentration during pregnancy achieved by in-vitro fertilization is strongly correlated to the number of growing follicles in the treatment cycle

In order to analyse the relationship between the ovarian responseto stimulation in in-vitro fertilization (IVF) treatment cyclesand relaxin concentrations during subsequent pregnancies, 31healthy women pregnant after IVF treat ment were studied prospectively.The maximum number of follicles observed from day –4 today –2 in relation to ovum retrieval and the number ofoocytes recovered were recorded. In addition, blood sampleswere drawn in the follicular phase, the luteal phase, earlypregnancy and at gestational weeks 12, 16, 20, 27 and 35 toassess oestradiol, progesterone, human choriomc gonadotrophinand relaxin. The maximum numbers (mean±SEM) of folliclesobserved and oocytes recovered were 9.0±0.6 and 6.1±0.5respectively. The supraphyslological mean relaxin values werestrongly correlated to the maximum number of follicles observed(r=0.72, P <0.0001) and the number of oocytes recovered (r=0.64,P <0.0001), indicating that the source of increased relaxinproduction during IVF pregnancy might be the ovary. These resultsare supported by experimental data. In the present study, theoccurrence of multiple pregnancy was not associated with higherrelaxin concentrations, which is further support for the hypothesisthat the ovary is the main source of serum relaxin.     

Obstetric outcome of pregnancies after the transfer of cryopreserved and fresh embryos obtained by conventional in-vitro fertilization and intracytoplasmic sperm injection.

This study reports the obstetric outcome of pregnancies obtained after the transfer of cryopreserved or fresh embryos where the initial procedure was standard in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Pregnancies obtained after frozen IVF (n = 245) or frozen ICSI (n = 177) were compared with a control group of pregnancies after fresh embryo transfer in standard IVF (n = 245) and ICSI (n = 177) cycles were selected as controls. The controls were matched according to maternal age, parity and date of embryo transfer. In the standard IVF group, the biochemical pregnancy rates in the cryopreserved and fresh groups were 18.8 and 9.8% respectively (P < 0.01). In the ICSI group, the biochemical pregnancy rates in the cryopreserved and fresh groups were 16.4 and 6.8% respectively (P < 0.01). The miscarriage rates were comparable between the cryopreserved and fresh groups. However, in the frozen ICSI group the miscarriage rate (26.0%) was significantly higher than in the frozen conventional IVF group (13.1%) (P = 0.001). The frequencies of preterm deliveries, infants with very low birthweight and intrauterine deaths were similar in the groups. The low birthweight rates in the frozen IVF (16.1%) and ICSI (12.1%) groups were significantly lower than those in the fresh IVF (32.2%) and ICSI (32.7%) groups (P < 0.001). The major malformation rates in the frozen IVF (2.4%) and ICSI (2.9%) groups were not different from the major malformation rates in the fresh IVF (4.5%) and ICSI (2.4%) groups. In conclusion, the cryopreservation process had no negative impact on the outcome of pregnancies over 20 weeks of gestation. Long-term follow-up studies are needed in order to prove the safety of the freezing-thawing process.     

Comparison of two recombinant follicle-stimulating hormone preparations in in-vitro fertilization: a randomized clinical study.

A randomized comparison of two recombinant human follicle-stimulating hormone (recFSH) preparations (Gonal-F and Puregon) in ovarian stimulation for in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was carried out at the Infertility Clinic of the Family Federation of Finland. A total of 348 women (aged 22-43 years) suffering from infertility due to miscellaneous causes was recruited. Of these, 344 underwent stimulation using equal starting doses (150 IU/day: Gonal-F n = 164, Puregon n = 158 or 300 IU/day: Gonal-F n = 8, Puregon n = 14) after down-regulation with intranasal buserelin from the mid-luteal phase. Similar clinical pregnancy rates were achieved with both preparations; 33.5% per cycle and 37.4% per embryo transfer (24.5% one-embryo and 75.5% two-embryo transfers, n = 147) with Gonal-F (150 IU/day) and 32.9% per cycle and 36.4% per embryo transfer (30.1% one-embryo and 69.9% two-embryo transfers, n = 145) with Puregon (150 IU/day). The ongoing cumulative pregnancy rates after frozen-thawed embryo transfer were 35.4% with Gonal-F and 37.7% with Puregon. Six cycles were cancelled because of a low response (three in each group). Similar numbers of oocytes were obtained in both groups; 13.0 with 150 IU/day and 6.1 with 300 IU/day Gonal-F, and 12.4 with 150 IU/day and 7.1 with 300 IU/day Puregon. The fertilization and cleavage rates and the incidence of moderate or severe ovarian hyperstimulation syndrome (Gonal-F, 2.0% and Puregon, 0.7%) were also similar. Gonal-F and Puregon were equally and highly effective in stimulation for IVF and ICSI.     

The effect of anxiety and depression on the outcome of in-vitro fertilization.

BACKGROUND: The study aim was to clarify the role of anxiety and depression on the outcome in assisted reproductive treatment. Previous studies on this topic have shown contradicting results, which may have been caused by population characteristics, the design of the study, or small sample sizes. METHODS: In a multicentre prospective study, 291 out of 359 (81%) consecutively invited women agreed to participate. Before down-regulation by means of gonadotrophin-releasing hormone (GnRH) analogues in a long IVF protocol, patients were asked to complete the Dutch version of the State and Trait Anxiety Inventory to measure anxiety, and the Dutch version of the Beck Depression Inventory (BDI) to measure depression. Multiple logistic regression analysis was used to analyse known predictors of pregnancy and psychological factors and their relationship with treatment outcome. RESULTS: A significant relationship was shown between baseline psychological factors and the probability to become pregnant after IVF/intracytoplasmic sperm injection (ICSI) treatment, controlling for other factors. State anxiety had a slightly stronger correlation (P = 0.01) with treatment outcome than depression (P = 0.03). CONCLUSIONS: Pre-existing psychological factors are independently related to treatment outcome in IVF/ICSI, and should therefore be taken into account in patient counselling. Psychological factors may be improved by intervention, whereas demographic and gynaecological factors cannot. Future studies should be directed towards underlying mechanisms involved and the role of evidence-based distress reduction in order to improve treatment results.     

Endocrinology: Pre-ovulatory progesterone growth rate in patients treated with gonadotrophin-releasing hormone agonist and outcome of in-vitro fertilization

The present study was undertaken to assess whether the increasein serum progesterone concentration following the administrationof human chorionic gonadotrophin (HCG) may have predictive valueon the in-vitro fertilization (IVF) success rate. Progesteroneconcentration on the day of HCG administration and the increasein progesterone concentration on the following day were evaluatedin 140 consecutive patients undergoing IVF with embryo transfer.Stimulation protocol in all study patients entailed intranasaladministration of short-acting gonadotrophin-releasing hormoneagonist (GnRHa) buserelin and human menopausal gonadotrophin.A pregnancy rate of 37.2% was achieved when at least three embryoswere transferred. The only significant difference between conceptionand non-conception cycles was found in serum progesterone concentrationsafter HCG administration (P < 0.01), whereas the mean progesteroneconcentration on the day of HCG did not differ. No differencein other hormonal or cycle parameters was observed. The increasein progesterone concentration was significantly greater in thegroup of patients who achieved pregnancy than in the group whodid not (2.2 ± 0.2 versus 1.6 ± 0.1 ng/ml, respectively;P < 0.01). A critical breakpoint in serum progesterone wasarbitrarily determined at 1 ng/ml. An increase in progesteroneconcentration 1 ng/ml when three or more embryos were transferredwas associated with a positive predictive value for pregnancyof 40.4% (sensitivity of 94.7%), whereas a negative predictivevalue of 86.7% was obtained when this value was <1 ng/ml.These findings indicate that an adequate rise in serum progesteronefollowing HCG administration provides useful information aboutthe possible outcome of the treated cycle.     

Pregnancy: Heterotopic abdominal pregnancy following in-vitro fertilization/embryo transfer presenting as massive lower gastrointestinal bleeding

We present a case that, as far as we know, is the first reportof lower gastrointestinal haemorrhage as a complication of heterotopicpregnancy induced by artificial reproductive technology. Theheterotopic abdominal pregnancy caused erosion of the intestinalwall and massive rectal bleeding, 8 weeks after in-vitro fertilization/embryotransfer. The source of the bleeding could not be identifieddespite comprehensive investigation including gastroscopy, ultra-sonography,sigmoidoscopy, ⁹⁹Tc (technetium) scanning and angiography. Tagged-erythrocyteisotope scanning revealed an abnormal concentration in the leftlower quadrant, compatible with active bleeding in the areaof the terminal ileum. Laparotomy disclosed a heterotopic abdominalpregnancy, causing erosion of the intestinal wall at this site.As assisted reproductive technologies become more and more commonthis rare complication of intestinal erosion should be keptin mind in cases of lower gastrointestinal bleeding.     

Shortened exposure of oocytes to spermatozoa improves in-vitro fertilization outcome: a prospective, randomized, controlled study.

A prospective, randomized study of 158 patients undergoing in-vitro fertilization (IVF) and embryo transfer was conducted to evaluate whether a shortened exposure of oocytes to spermatozoa enhances oocyte development, and subsequently influences the IVF outcome. A comparison was made between conventional treatment time and shorter exposure of retrieved oocytes to spermatozoa. Fertilization and cleavage rates, embryo quality, implantation and pregnancy rates in the study group (short exposure) versus controls (standard IVF procedure) were evaluated. Fertilization (56 versus 61%) and cleavage rates (96 versus 92%) were similar in the two groups respectively. However, embryo quality was significantly higher in the study group (P < 0.05). Moreover, the pregnancy and implantation rates were significantly increased (42.4 versus 26% per embryo transfer, and 16 versus 10% respectively; P < 0.05). Our results demonstrated that shorter exposure of oocytes to spermatozoa is superior to the standard time in IVF and may have a favourable effect on implantation rates by improving embryo quality.     

Implantation: Embryo score to predict implantation after in-vitro fertilization: based on 957 single embryo transfers

The purpose of this study was to devise an embryo score to predictthe likelihood of successful implantation after in-vitro fertilization(IVF). Unlike most studies dealing with the influence of embryostage and morphology on pregnancy, our study was based on singlerather than multiple embryo transfers. A total of 957 singleembryo transfers were carried out. No delivery was obtainedafter any of the 99 transfers using 1-cell embryos or embryosobtained after delayed fertilization. In the remaining 858 transfers,the embryos had cleaved. Higher pregnancy rates were obtainedwith embryos displaying no irregular cells (11.7 versus 6.9%;P < 0.01) and embryos displaying no fragmentation (11.5 versus8.1%; P < 0.05). The 4-cell embryos implanted 2-fold moreoften than embryos with more or less cells (15.6 versus 7.4%;P < 0.01). Based on these observations, we devised a 4-pointembryo score in which embryos are assigned 1 point each if they(i) are cleaved, (ii) present no fragmentation, (iii) displayno irregularities, and (iv) have four cells. Both pregnancyrate and take home baby rate were significantly correlated withembryo score. Each point of this score corresponds to a 4% increasein pregnancy rate. Interestingly, pregnancy rate was significantlylower in women aged >38 years (8.2 versus 11.4%; P < 0.05),even though embryo quality was similar regardless of age. Singleembryo transfer allowed us to define a simple and useful embryoscore to choose the best embryo for transfer to optimize IVFand embryo transfer outcome. The use of this embryo score coulddecrease multiple pregnancies after multiple embryo transfers.     

Embryo transfer under ultrasound guidance improves pregnancy rates after in-vitro fertilization

Between October 1998 and January 1999, we examined the influence of ultrasound guidance in embryo transfer on pregnancy rate in 362 patients from our in-vitro fertilization (IVF)-embryo transfer programme. These patients were prospectively randomized into two groups: 182 had ultrasound-guided embryo replacement, and 180 had clinical touch embryo transfer. There were no statistically significant differences between the two groups with respect to age, cause of infertility and in the characteristics of the IVF cycle. The pregnancy rate was significantly higher among the ultrasound-guided embryo transfer group (50%) compared with the clinical touch group (33.7%) (P < 0.002). Furthermore, there was also a significant increase in the implantation rate: 25.3% in the ultrasound group compared with 18.1% in the clinical touch group (P < 0.05). In conclusion, ultrasound assistance in embryo transfer significantly improved pregnancy and implantation rates in IVF.     

Pregnancy: Heterotopic pregnancy obtained after in-vitro fertilization and embryo transfer following bilateral total salpingectomy: case report

Heterotopic (coexistent ectopic and intra-uterine) pregnancyis common following in-vitro fertilization and multiple embryotransfer. Total bilateral salpingectomy is generally consideredto eliminate the risk of ectopic, and hence heterotopic pregnancy.This is, however, not strictly correct as it does not eliminatethe risk of interstitial tubal pregnancy. This is the firstreported case of a heterotopic pregnancy following total bilateralsalpingectomy. The diagnostic pitfalls and a suggested methodof avoiding them are discussed.