High Multiple Pregnancy Rate Research Articles

Cervical insemination versus intra-uterine insemination of donor sperm for subfertility

Insemination with donor sperm is an option for couples for whom in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI) has been unsuccessful, couples with azoospermia and for single women or same sex couples. Insemination of sperm can be done via cervical (CI) or intra-uterine (IUI) routes. IUI has been considered potentially more effective than CI as the sperm bypasses the cervical mucus and is deposited closer to the fallopian tubes. The cost and risks of IUI may be higher because of the need for sperm preparation and the introduction of foreign material into the uterus. Donor sperm used for artificial insemination is mainly cryopreserved, due to concerns about HIV transmission. However, cycle fecundity is higher for fresh sperm. Insemination is often combined with ovulatory stimulation, with either clomiphene or gonadotrophin. There may be risks associated with these therapies, such as higher multiple pregnancy rates. To determine whether pregnancy outcomes are improved using intra-uterine insemination in comparison to cervical insemination in women undergoing artificial insemination with donor sperm. The following databases were searched: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL (The Cochrane Library) , MEDLINE, EMBASE, CINAHL and the reference lists of articles retrieved. Randomised controlled trials comparing IUI with CI were included. Crossover studies were included if pre-crossover data was available. Study quality assessment and data extraction were carried out independently by two review authors (DB, JM). Authors of studies that potentially met the inclusion criteria were contacted, where possible if additional information was needed. The search strategy found 232 articles. Fifteen studies potentially met the inclusion criteria. Four studies were included in this review. All the included studies used cryopreserved sperm in stimulated cycles. In two studies 134 women had gonadotrophin-stimulated cycles and in two studies 74 women had clomiphene-stimulated cycles. The evidence showed that IUI after 6 cycles significantly improved live birth rates (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.02 to 3.86) and pregnancy rates (OR 3.37, 95% CI 1.90 to 5.96) in comparison to cervical insemination. There was no statistically significant evidence of an effect on multiple pregnancies (OR 2.19, 95% CI 0.79 to 6.07) or miscarriages (relative risk (RR) 3.92, 95% CI 0.85 to 17.96). The findings of this systematic review support the use of IUI rather than CI in stimulated cycles using cryopreserved sperm for donor insemination.

Évaluation prospective du transfert sélectif d’un embryon : deux années d’expérience

ObjectiveMultiple embryo transfer is responsible for a high rate of multiple pregnancies (ICSI), with subsequent risks of premature birth and perinatal death. This prospective non randomized study aimed to assess the ability of an elective single-embryo transfer (eSET) policy to reduce the twin pregnancy rate, compared to a double embryo transfer (DET) approach. Patients and methodsBetween March 2005 and May 2006, 180 eligible women were proposed to benefit from an eSET transfer rather than a DET. Inclusion criteria were (i) age less than 37 years old; (ii) at least two good quality embryos available (three to five cells at day 2 or six to nine cells at day 3; less than 20% fragmentation and the absence of multinucleates blastomeres), after IVF or ICSI and (iii) no more than one previous failed treatment cycle. Outcome analysis included cycles with frozen-thawed embryo transfer (FET). ResultsAccording to patients’ decision, 107 and 73 women had an eSET (59.4%) and a DET (40.6%) respectively. No differences were found between eSET and DET groups regarding demographics and biologicals parameters. The clinical pregnancy rate (PR) per transfer was 43.9% in eSET group and 57.5% in DET group (p=0.07). The twin pregnancy rates were 0 and 14.3%, in eSET and DET groups, respectively (p=0.007). The cumulative PR per patient, including the outcome of performed FET cycles, was 63.6% in eSET group and 61.6% in DET group. In this case, the cumulative twin pregnancy rates were 2.9 and 15.6% in eSET and DET groups, respectively (p=0.02). Discussion and conclusionOur data show that in a selected population of women, transferring one fresh embryo and then, if required, one or two frozen-thawed embryos significantly reduces the twin pregnancy rate without decreasing the overall pregnancy rate. This study supports the policy of eSET in this subgroup of patients.

Single embryo transfer

Multiple pregnancies present significant problems for mothers and babies. The incidence of twin pregnancies has increased dramatically in the last 30 years, linked to the development of assisted reproductive technologies including in vitro fertilisation (IVF). The occurrence of multiple pregnancies after IVF is directly related to the number of embryos replaced during treatment. Policies to reduce the number of multiple pregnancies through limiting the numbers of embryos transferred have been successfully introduced in some parts of Europe. Anxieties that pregnancy rates would decline significantly after introduction of a policy of single embryo transfer have not been realised, particularly when the pregnancies derived from the transfer of additional cryopreserved embryos are taken into consideration. Obstacles to the introduction of such a policy in the UK relate to the commissioning arrangements for IVF and the competitive commercial environment in which IVF is provided. Continued high multiple pregnancy rates are not acceptable. IVF children should be given the best chance possible of safe delivery, at term, as singletons.

Acceptance of single-embryo transfer by patients

In New Zealand, patient motivation to accept single-embryo transfer can be measurably changed within a short period of time if patients are provided with credible clinical written and verbal communication, in addition to funding incentives from the Ministry of Health.

O-85: ART practice patterns and the impact of embryo transfer guidelines in the United States

O-85: ART practice patterns and the impact of embryo transfer guidelines in the United States

Cerebral palsy in children born after IVF in Sweden 1982–1995: Type of CP and maternal/obstetrical characteristics are similar to those in non‐IVF children with CP

Background. An increased risk of cerebral palsy (CP) after in‐vitro fertilisation (IVF) has previously been reported from a Swedish cohort including all children born after IVF in 1982–1995. The background CP prevalence of 0.15% was increased to 0.55%. Children born after IVF had a 3.7‐fold increased risk of cerebral palsy compared with non IVF children. An increased risk (2.8 fold), of CP was also found in the IVF singletons. The aim of this study was to further describe background factors and morbidity details regarding children with CP born after IVF.Methods. In the previous report 31 cases of CP were identified among children born after IVF (n = 5680), compared to the expected number, nine. In this study we compared the type and severity of CP and maternal and perinatal characteristics of the 31 children with CP born after IVF with 44 non‐IVF children with CP. Data were collected from four different sources. Data concerning treatment details were collected from all Swedish IVF clinics and data concerning maternal background factors, pregnancy complications, delivery and immediate post‐natal outcome from the Swedish Medical Birth Registry. All Swedish habilitation centres provided data concerning the CP syndromes. Finally, data were collected from the Swedish Hospital Discharge Registry, which covers all public in‐patient care in Sweden, on whether these children, in addition to CP, had been treated for mental retardation (MR) or epilepsy (EP). Using the specific personal identification number given to every Swede, data were cross‐linked. Singletons were matched for sex, year of birth and birth hospital, whereas twins were just matched for year of birth.Findings. The method of conception was conventional IVF in 29/31 children, intracytoplasmic sperm injection in one IVF twin and conventional IVF with frozen embryos in one IVF triplet. All twins except one non‐IVF twin pair and all IVF triplets were from different sets. The median maternal age and range were 30 (21–42) years. IVF mothers were more likely to be over 35 years of age and primiparous than non‐IVF mothers, although the differences were not statistically significant (OR 2.6; 95% CI 0.8–8.4 and OR 1.4; 95% CI 0.5–4.9, respectively). No specific antepartum risk factor could be identified. Most children with CP were of male sex, were born preterm or were the result of a multiple pregnancy. Very preterm birth was seen more often among IVF singletons than among non‐IVF singletons (OR 6.5; 95% CI 1.0–42.2).Spastic/ataxic diplegia, followed by spastic hemiplegia, were the most commonly seen CP syndromes both among the IVF and non‐IVF children, irrespective of single or twin birth. As expected, most children with spastic/ataxic diplegia were born preterm and term infants were in majority in the spastic hemiplegia group. Both these CP syndromes were seen more often among twins. Four IVF singletons and four IVF twins had CP + MR compared to three and seven non‐IVF singletons or twins respectively. The corresponding numbers of IVF children with CP + EP were five singletons and four twins compared to four non‐IVF singletons and three non‐IVF twins. No statistically significant differences between IVF and non‐IVF children were found in respect to type of CP or concerning CP in combination with MR or EP.Interpretations. No differences in type, severity of CP or background characteristics were found between children born after IVF and non‐IVF children. Our interpretation is that aetiological factors for CP do not differ, but that the increased prevalence of CP seen after IVF is due to the high multiple pregnancy rate and prematurity.

ICMART World Report on In Vitro Fertilization 2000: How Does the United States Compare?

To compare the results of IVF from different countries and regions of the world with those obtained in the United States for the year 2000. Retrospective survey of regional, national and individual clinic registers of IVF results, including the SART/CDC registry. Data forms from the International Committee for Monitoring Assisted Reproductive Technology (ICMART) were sent in English with instructions to regional and national registries and selected individuals around the world. Returned surveys were analyzed using sums, percentages, means and regression analysis. The CDC returned the data for the US.Data were collected from individual country summaries and not by individual patients. Pregnancy rates and delivery rates were calculated per aspiration. 1,429 clinics in 49 countries reported, representing approximately 2/3 of the 2,200 IVF clinics in the world. The United States (US) had 408 clinics. The mean centers’ activity varied greatly, with many small centers with less than 100 cycles in United States (36%) compared to Europe (15%), whereas centers with more than 500 cycles for those regions respectively were 11% and 37%.The clinics worldwide reported 367,731 aspirations, including 191,109 for IVF, 175,147 for ICSI and 1,475 for GIFT. There were 52,875 frozen embryo transfers (FET), and 14,848 oocyte donor transfers. The US had 63,861 aspiration cycles, including 28,940 IVF, 34,430 ICSI and 491 GIFT. The US did not report FET, but had 6,941 oocyte donation transfer cycles. Europe represented by far the largest activity with 207,004 aspirations and 40,154 FET. For conventional IVF average pregnancy rate (PR) and delivery rate (DR) were 26.7% and 18.6% respectively worldwide, compared with 38.5% and 31.0%, respectively, in the US. For ICSI, world average PR and DR were 27.7% and 20.4%, respectively, compared with 35.2% and 28.6% in the US. On a world basis, 49.4% of the women were over age 34 and 14.4% over 39, compared with the US where the percentage was 54.9% and 18.0%. For ICSI the figures were 47.4% and 14.2% respectively, worldwide, and 51.2% and 15.3% in the US. The mean number of embryos transferred for IVF and ICSI were 2.5 and 2.7, respectively, compared to 3.0 and 3.1 in the US. The proportion of twin pregnancies was 26.9% for IVF and 26.2% for ICSI worldwide, compared to 31.7% and 30.5%, respectively, in the US. Triplet pregnancies were 2.8% for IVF and 2.9% for ICSI worldwide compared with 4.7% and 3.9%, respectively, in the US. The triplet rate was closely associated with the number of transferred embryos, but the pregnancy rate was not, except in the United States and Chile. Oocyte donation had a higher PR and DR at 41.9% and 32.5%, respectively, worldwide, compared with 51.7% and 43.5% in the US. Approximately 2/3 of the IVF cycles in the world are reported and compared to results in the US. The US has higher pregnancy rates and also higher multiple pregnancy rates, likely as a result of transferring more embryos than many countries. While extreme caution must be exercised because of limitations of the study design, data collection and analysis in comparing different regions of the world, such data are very useful in increasing our understanding of clinical utilization of IVF and its outcomes.

Further considerations on natural or mild hyperstimulation cycles for intrauterine insemination treatment: effects on pregnancy and multiple pregnancy rates

The high iatrogenic multiple pregnancy rate associated with intrauterine insemination (IUI) in hyperstimulated cycles is becoming less acceptable. Therefore we investigated data from an earlier prospective trial with regard to the specific question of whether the application of mild hyperstimulation in IUI cycles could be an alternative strategy for obtaining acceptable pregnancy rates while preventing a high multiple pregnancy rate, compared with natural cycles for IUI. Pregnancy outcome of 310 natural and 334 mildly hyperstimulated cycles for IUI in 171 couples with unexplained or mild male factor subfertility was analysed on a patient level with random coefficient models. Pregnancy rates were similar: 35 and 39.8% per couple in the natural and mildly hyperstimulated cycles respectively (P = 0.60). Multiple pregnancies, all twin pregnancies, were conceived significantly more frequently in the mild hyperstimulation group (27% of the pregnancies) than in the natural cycle group (4% of the pregnancies) (P = 0.01). All multiple pregnancies in the hyperstimulation group were conceived in multifollicular cycles. Multifollicular development was strongly associated with the application of mild hyperstimulation only (odds ratio 21.14, 95% confidence interval 8.15-54.79). The application of a mild hyperstimulation protocol as an alternative to a standard hyperstimulation protocol for IUI does not result in higher pregnancy rates than IUI in the natural cycle, while at the same time multiple pregnancies cannot be avoided. Therefore, there is no place for the use of gonadotrophins in IUI treatment.

Pregnancy rate, multiple pregnancy rate, and embryo quality: Clues for single blastocyst transfer from double blastocyst transfer in an unselected population

Objective: Minimizing multiple pregnancy is a priority in assisted reproduction. As implantation rates are critical to success and reduce multiple pregnancy, we investigated whether blastocyst grade determined implantation rate following double blastocyst transfer in unselected cases. Materials and Methods: We studied 69 three-cleavage stage embryo transfers and 64 two-blastocyst transfers. Two blastocysts, or one when two blastocysts were not available, were transfered after evaluating the grade of blastocysts. The difference in pregnancy and implantation rates to patient age, the number of retrieved oocytes and grade of blastocysts were analyzed. Results: Blastocyst and grade 3AA rates per fertilized egg were 50.3% and 26.0%, respectively. Following two-blastocyst transfer, pregnancy rate per transfer, implantation rate per embryo, and multiple pregnancy rate per pregnancy were 39.1%, 26.5%, and 24.0%, respectively. Two-blastocyst transfer achieved implantation more often than three-cleavage-stage embryo transfer, but did not reduce multiple pregnancy. Pregnancy, implantation, and multiple pregnancy rates did not reflect maternal age. Higher pregnancy and implantation rates per transfer were attained for with six or more oocytes retrieved or transfer of two-blastocyst graded 3AA or higher especially when two or more blastocysts graded 3AA or higher are available, but the latter showed a high multiple pregnancy rate (38.5%). Conclusions: Single embryo transfer could be carried out when two or more blastocysts of grade 3AA or higher have been developed. (Reprod Med Biol 2005; 4: 153-160).

Emerging drugs in assisted reproduction

Infertility affects ∼ 15% of couples of reproductive age. In assisted reproductive technology (ART), medications play a crucial role in stimulating ovaries to produce several oocytes and prepare the endometrium to be receptive after replacing one or more embryos into the uterine cavity. The availability of recombinant human follicle stimulating hormone, luteinising hormone and human chorionic gonadotrophin; of gonadotrophin-releasing hormone (GnRH) agonists and antagonists; and of luteal supplementation with progesterone have allowed the tailoring of several stimulation schemes, which have enhanced the pregnancy outcome after ART treatment. However, the remaining risk of ovarian hyperstimulation syndrome, the still low implantation rates, the unacceptably high rates of multiple pregnancies and the daily parenteral administration of medications do not constitute the features of a patient-friendly procedure. Therefore, a number of molecules with gonadotrophin-like activity, inhibition of GnRH receptor ability, or endometrium receptivity enhancement properties are currently under active investigation. Orally bioactive therapeutic preparations, in particular, may revolutionise in vitro fertilisation (IVF) treatment in the near future. Nevertheless, the implementation of mild ovarian stimulation protocols with single embryo transfer policy and further development of oocyte in vitro maturation techniques may lead to a less drug orientated IVF treatment.

Would legislation imposing single embryo transfer be a feasible way to reduce the rate of multiple pregnancies after IVF treatment?

Due to increased maternal and fetal risks, there is a strong opinion in favor of single embryo transfer (SET) in order to reduce the high multiple pregnancy rate after IVF. We have evaluated the effects on pregnancy rate and twinning of recent Swedish legislation on SET. The study comprised three embryo transfer (ET) periods: period I, autumn 2001-spring 2002 (n=609), with a double embryo transfer (DET) policy; period II, autumn 2002 (n=320), a transitional period; and period III, January-September 2003 (n=433), with a SET policy. During the three periods, the SET rates were 25.1, 55.5 and 72.7%, respectively (Kruskal-Wallis test P<0.0001). There was no difference in clinical pregnancy rates (33.3, 32.8 and 37.4%, respectively) (P=0.4), but the twinning rate was significantly lower in the third period (6.2 versus 22.6% in period I and 16.3% in period II) (P<0.005). After introducing a SET policy, the expected decline of twinning was met at an unchanged clinical pregnancy rate. Thus, the SET legislation had no negative consequences for the couples. On the contrary, the lower rate of twinning is expected to reduce the severity and rate of pregnancy complications after IVF. Whether legislation or voluntary SET is the most feasible way to proceed, in order to reduce the multiple pregnancy rates after IVF, can be debated.

Identification of viable embryos in IVF by non-invasive measurement of amino acid turnover.

IVF is limited by low success rates and an unacceptably high multiple pregnancy rate. These outcomes would be improved significantly if a single embryo of high viability could be replaced in each treatment cycle, but widespread acceptance of such a policy is hindered by the lack of predictive factors for embryo selection. We have conducted a retrospective clinical study of a novel non-invasive method of embryo selection based on the depletion/appearance of amino acids in the culture medium. Fifty-three cycles of IVF treatment using ICSI were studied. Embryos were cultured for 24 h in 4 microl drops of medium containing a physiological mixture of 18 amino acids. The spent medium was analysed for amino acid content by high performance liquid chromatography. The turnover of three amino acids, Asn, Gly and Leu, was significantly correlated with a clinical pregnancy and live birth. These correlations were independent of known predictors, such as female age, basal levels of FSH, embryo cell number and embryo morphological grade. Non-invasive assay of amino acid turnover has the potential to improve significantly the prospective selection of the most viable embryos, or single embryo, for replacement in an IVF cycle.

What is the most relevant standard of success in assisted reproduction? Is BESST (birth emphasizing a successful singleton at term) truly the best?

There is much variability and no consensus on the definition of the most relevant outcome parameter after assisted reproduction technology (ART). Descriptive reports, such as annual statistics from national registries on the success of ART programmes, should present treatment success in terms of live birth per ovarian stimulation started, as this is the most relevant information for patients and doctors alike. Addressing concerns about the high rate of multiple pregnancies, rescaling the outcome of ART in large programmes and national audits to the singleton, live birth, might trigger a global change of attitude towards elective single embryo transfer in addition to any legal restrictions imposed. For clinical studies, the outcome measure will depend on the hypothesis tested, and investigators should remain free to choose the appropriate primary outcome measure.

Toward single embryo transfer policy

Toward single embryo transfer policy

Stimulated Intrauterine Insemination: Efficient, cost-effective, safe?

A retrospective report of pregnancy and birth rates achieved in 1010 cycles of stimulated intrauterine insemination (SIUI). Over the years there has been an increasing emphasis on safety, particularly towards reducing the number of high order multiple pregnancies. SIUI is a complex form of assisted conception and requires a high level of clinical judgement to maintain an optimal balance between maximising pregnancy and birth rates and minimising complications, of which the most serious is multiple pregnancy. Extrapolating from these results, it is concluded that a well managed SIUI programme that selects patients appropriately, monitors them intensively and has in place effective strategies to manage over-responders safely, should be able to deliver at least a 15% live birth rate per cycle started with only a 5% cycle cancellation rate. Although SIUI birth rates are lower than IVF rates, the much lower cost of SIUI means that this treatment can be more cost-effective than IVF. However SIUI remains more risky than IVF and, despite careful management, high order multiple pregnancy rates will occasionally occur. It is estimated that the rate of unavoidable high order multiple pregnancies (triplets and above) is 4 per 1000 cycles started.

Two versus three embryos for transfer on day 3: influence of female age and embryo quality on outcome

Objective: The objective of this study was to determine the optimal number of embryos to transfer on day 3 in females up to age 38. The dual goals are to maintain a high pregnancy rate and minimize the multiple pregnancy rate. Design: This is a retrospective study with data collected from January 1999 through March 2003. All embryo transfers were performed on day 3 after oocyte retrieval and excluded any oocyte donor cases. Patients were classified by age into one of two groups: females <35, or females >35 and <38. Outcome comparisons (ongoing pregnancy rates defined as presence of a heart beat at 9 weeks gestation) were made by Chi-Square analysis. Only patients with at least 3 embryos at transfer were included in the data analysis. Materials and Methods: All patients underwent an ovarian stimulation protocol using either a GnRH agonist prior to stimulation with gonadotropins, or a GnRH antagonist following gonadotropin stimulation. Oocyte retrieval was performed 36 hrs post hCG administration and embryos were transferred approximately 72hrs post oocyte retrieval. Patients utilizing either standard IVF or ICSI were included in this study. Embryos were cultured in commercially prepared media and graded for quality (cell stage, degree of fragmentation, symmetry of blastomeres) immediately prior to transfer. The highest quality embryos available were chosen for transfer. Results: For the <35 age group, it was found that patients receiving 2 high quality embryos (lead embryo at least 8 cells and of the highest grade) at transfer (n=141) had an ongoing pregnancy rate of 55% while those receiving 3 such embryos (n=196) had an ongoing rate of 56% (P>.05). The singleton, twin and triplet rate for pregnancies of patients receiving 2 embryos was 62%, 38%, and 0%, respectively. Patients receiving 3 embryos had a singleton, twin, and triplet rate of 55%, 34 % and 11%, respectively. When the >35 and <38 age group was examined, it was found that the ongoing pregnancy rate of those patients receiving 3 embryos meeting the same criteria (lead embryo at least 8 cells of the highest grade) (n=123) was 53%. Those receiving 3 embryos had singleton, twin and triplet rates of 55%, 34%, and 8%, respectively (P>.05 when compared to <35 group). As there were no patients in this age group that electively chose only 2 embryos for transfer, these data cannot be directly compared to those of the <35 group receiving 2 embryos. Conclusion: These data raise an interesting possibility for the age group between 35 and 38. It is clear that in the under 35 age group, 3 embryos offer no advantage over 2 embryos when high quality embryos are available for transfer. Moreover, the addition of a third embryo in this group does not increase the overall pregnancy rate-only the high order multiple pregnancy rate (triplets). The fact that the 35–38 age group receiving 3 embryos displayed almost identical pregnancy rates as the under 35 group receiving 3 embryos and that the singleton, twin and triplet rates were not different between the groups suggests that even the older group may benefit from having only 2 high quality embryos transferred. These data suggests doing so would not compromise overall pregnancy rates but would have the benefit of reducing the high order multiple rates. Furthermore, these data fully support the SART guideline of transferring only 2 embryos in younger patients that have a good prognosis. In addition, these data suggest that extending that guideline to include patients up to 38 with a good prognosis may be justified.

Reduction of high order multiple pregnancies by critically assessing blastocyst implantation potential

Objective: High multiple pregnancy rates remain a concern with blastocyst culture and transfer. Many IVF programs are hesitant to transfer only 1 blastocyst, therefore critically assessing blastocyst implantation potential should clarify the maximum number of high quality blastocysts to transfer while maintaining a high pregnancy rate. The objective of this study is to determine the number of high quality blastocysts to transfer, while minimizing high order multiple pregnancies.

Mono-ovulatory cycles: a key goal in profertility programmes.

Mono-ovulatory cycles for women are optimal because singleton pregnancies have a better outcome than multiples. Multiple births began to increase in the 1950s after the first appearance of effective ovulation induction for the treatment of anovulation. Since the 1980s when ovulation induction and IVF were more broadly applied to the treatment of unexplained and persistent infertility, there has been an unprecedented rise in multiple births. Strategies to achieve mono-ovulation during treatment of anovulatory patients are distinct from those for the treatment of ovulating patients who have unexplained and persistent infertility. Anovulatory patients with hypogonadotrophic hypogonadism can be treated with exogenous pulsatile GnRH, which restores normal gonadotrophin secretion, ovulation rates and conception rates. The multiple pregnancy rate is not increased with GnRH treatment. In patients with normogonadotrophic anovulation, attention should be given to diet and exercise before any other interventions are considered. Pharmacological induction of ovulation can be achieved with antiestrogen, gonadotrophin or pulsatile GnRH treatment; antiestrogen is the first choice with gonadotrophin more widely used for clomiphene citrate (CC)-resistant patients. Obesity and polycystic ovaries are common in this group, so that gonadotrophin and GnRH treatment are associated with lower responses compared with hypogonadotrophic hypogonadism, and higher multiple pregnancy rates. Low dosage protocols are being tested that may lower the multiple birth rates. The role of drugs enhancing sensitivity to insulin, e.g. metformin, remains undetermined. Laparoscopic ovarian diathermy achieves conception rates that are equivalent to gonadotrophin treatment, with fewer multiple births. Augmenting normal ovulation processes for couples with unexplained and persistent infertility is less effective. Pregnancy rates are statistically significantly higher with CC but the size of the increase is not clinically important. CC with intrauterine insemination is associated with a clinically important effect on conception. Achieving mono-ovulation is more difficult in assisted reproductive technology cycles because success depends on maintaining the level of FSH above the threshold level longer than normal in order to increase the number of mature follicles. Milder stimulation for IVF and IVF in the untreated cycle show great potential, however, especially in view of the trend toward transfer of a single embryo in assisted reproductive treatment cycles.

Perinatal outcome and developmental studies on children born after IVF.

Since the first birth after IVF, many scientific papers have been published on the technical aspects of the IVF procedure, but few studies have addressed the issue of the perinatal outcome of IVF pregnancies and of the children's development and well-being. A high rate of adverse outcome has been demonstrated in a large group of IVF pregnancies. Prematurity, low birth weight and perinatal mortality are higher than in the general population. The majority of these complications are related to multiple births, but they are also found in singleton pregnancies. An analysis of the multiple risk factors involved in these complications is needed. The infertile status of IVF patients clearly plays a role in the risk of adverse outcome. Age and parity may be important factors. The role of IVF itself has not been demonstrated convincingly. The effect of ovarian stimulation deserves further study. Most of the studies published on the follow-up of IVF children are reassuring, but it is clear that these studies are not sufficient to eliminate without doubt any adverse effects on the well-being of IVF children. All IVF pregnancies should be followed with great care, not because they are more precious than spontaneous pregnancies, but because they are exposed to an increased risk of complications. The main problem of IVF remains the high rate of multiple pregnancies, including twins.

High rates of embryonic loss, yet high incidence of multiple births in human art: is this paradoxical?

Humans have low natural fecundity, as the probability of establishing a viable conception in any one menstrual cycle is 20–25% for a healthy, fertile couple. There are numerous underlying causes for this low rate of human fertility, not the least of which are intrinsic abnormalities within the oocyte and/or embryo, which likely account for greater than 50% of failed conceptions. During assisted reproduction technology (ART) interventions, controlled ovarian stimulation is used to obtain several oocytes in attempts to increase the likelihood of having at least one developmentally competent embryo available for transfer. However, current techniques for identifying the competent embryo(s) are by no means perfect. These limitations, coupled with pressures to maximize the chance of pregnancy, typically result in the transfer of multiple embryos. Not surprisingly, this practice has resulted in an unacceptably high rate of multiple pregnancies arising from ART. During the last few years, concerted efforts have focused on reducing these rates. Programs for ART are developing patient-specific policies, restricting the number of embryos to transfer. In addition, strategies are being adopted to improve the accuracy for selecting viable embryos for transfer. One such strategy involves further refinement of morphological criteria associated with improved viability by considering, for example, pronuclei disposition, nucleolar organization, and identification of the fast-cleaving embryos with only mononucleate blastomeres. Another strategy employs pre-implantation genetic diagnosis (PGD) whereby a biopsied blastomere is tested for ploidy using fluorescence in situ hybridization (FISH). A final strategy involves extending the duration of culture to the blastocyst stage, thereby allowing self-selection of those embryos capable of proceeding to blastulation and exclusion of those less viable embryos that succumb to developmental arrest. Together, these strategies are enabling fewer embryos of higher quality to be transferred. Accordingly, the overall pregnancy rate from ART continues to increase, while the rate of triplet and higher order multiple births continues to decline. Nevertheless, the high incidence of intrinsic developmental anomalies in human oocytes inevitably will continue to result in a high degree of embryonic loss in ART.