Cognitive and behavioural outcome of children born after IVF at age 9 years.

STUDY QUESTION: Do ovarian stimulation (OS) and the in vitro laboratory procedures affect offsprings' cognitive and behavioural outcome at 9 years? SUMMARY ANSWER: OS and the in vitro laboratory procedures or the combination of both were not associated with cognitive and behavioural outcome at age 9 years. WHAT IS KNOWN ALREADY: ART is not associated with an adverse short-term developmental outcome of the offspring, but limited knowledge is available on the offspring's long-term neurodevelopmental condition. STUDY DESIGN, SIZE, DURATION: A 9-year longitudinal, assessor-blinded, prospective follow-up study of 169 out of 215 singletons (79%) born between March 2005 and December 2006 was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Singletons born following IVF or ICSI with OS (n = 57), born after modified natural cycle IVF/ICSI (MNC-IVF/ICSI; n = 46) and born after natural conception to subfertile couples (Sub-NC; n = 66), were assessed at 9 years. This study design, with two ART groups and a subfertile reference group, allows for disentangling the effects of OS and ART procedures on developmental outcome. Cognitive outcome was evaluated with the Wechsler abbreviated scale of intelligence and the NEPSY-II. Behaviour was assessed with the child behaviour checklist (CBCL) and teacher report form (TRF). Univariable analyses and multiple linear regression models were used. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in intelligence quotient (IQ) scores between ART groups (mean IQ (95% CI): OS 114.8 (83.2-142.6); MNC 114.0 (90.2-140.8); Sub-NC 115.4 (87.9-141.2), P = 0.746). Multivariable analyses did not reveal a statistically significant association between ART group and total, verbal and performance IQ. CBCL and TRF scores did not differ significantly between ART groups (P = 0.090 and 0.507, respectively). Multivariable analyses did not demonstrate a statistically significant association between ART group and CBCL and TRF total, or internalising and externalising T-scores. No significant correlations between time to pregnancy (TTP)-a proxy for the severity of parental subfertility-and outcome measures were found (Spearman rho between -0.050 and 0.049, NS), which was confirmed with multivariable analyses. LIMITATIONS, REASONS FOR CAUTION: The attrition rate of 21% may be considered as a limitation of the study; however, after a follow-up period of 9 years, this rate is generally considered acceptable, and there were no significant differences in background characteristics between children with and without follow-up, making an attrition-related selection bias less likely. Another limitation of the study is the relatively small sample size, which could contribute to selection bias, hamper generalizability to the ART population and lead to false negative findings as a result of underpowering. An a priori power analysis on total IQ indicated that the OS-IVF/ICSI and Sub-NC groups should contain 64 children, confirming that our study including 57 and 66 children, respectively, was slightly underpowered. WIDER IMPLICATIONS OF THE FINDINGS: Our study indicated that OS and the in vitro laboratory procedures or the combination of both and TTP were not associated with cognitive and behavioural outcome at 9 years. These are reassuring results for both parents and clinicians involved in ART. STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the University Medical Center Groningen (UMCG), two graduate schools of the UMCG (BCN and SHARE) and the Cornelia Stichting. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.

Asthma in 9-year-old children of subfertile couples is not associated with in vitro fertilization procedures.

Asthma is a chronic reversible obstructive airway disease, which is common among children and leads to respiratory impairment. Studies showed that asthma is more common among children born after in vitro fertilization (IVF) than among spontaneously conceived children. However, it is unknown which component of the IVF procedure contributes to this putative link. Therefore, the aim of this prospective follow-up study was to differentiate the possible effect of ovarian hyperstimulation from that of the in vitro culture procedure on asthma and rhinitis in 9-year-old children conceived with IVF. The study comprised three groups of singletons: (I) conceived with ovarian hyperstimulation-IVF (COH-IVF, n = 95); (II) conceived with modified natural cycle-IVF (MNC-IVF, n = 48); and (III) naturally conceived to subfertile couples (Sub-NC, n = 68). Parents filled out the validated Dutch version of the asthma questionnaire of the International Study of Asthma and Allergies. Asthma prevalence in the groups did not differ: COH-IVF n = 8 (8%); MNC-IVF n = 0 (0%); and Sub-NC n = 4 (6%). Adjustment for confounders did not alter the results.Conclusion: Neither ovarian hyperstimulation nor the in vitro culture procedure was associated with asthma and rhinitis at 9 years. IVF children had a similar prevalence of asthma compared with children conceived naturally by subfertile couples.Trial registration: ISRCTN76355836 What is Known: • An increased risk for asthma has been observed in children born after in vitro fertilization at preschool and school age. • The association between IVF and asthma may be partly explained by parental subfertility. What is New: • IVF children do not have a higher prevalence of asthma than children of subfertile couples conceived naturally. • Ovarian hyperstimulation used in IVF is not associated with asthma in 9-year-old children of subfertile couples.

Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not.

STUDY QUESTION: Does ovarian hyperstimulation, the in vitro procedures required for in vitro fertilization (IVF)/ intracytoplasmic sperm injection or the combination of both, affect the neurological outcome of 4-year-old singletons? SUMMARY ANSWER: Ovarian hyperstimulation, the in vitro procedure and the combination of both, were not associated with the worse neurological outcome in 4-year-old singletons. WHAT IS KNOWN ALREADY: Assisted reproduction techniques (ARTs) are not associated with neurological dysfunction during the first post-natal years; however, effects on the long-term neurological outcome are still inconclusive. An increased time to pregnancy (TTP, a proxy for the severity of subfertility) has been associated with a less optimal neurological condition at age 2. The present study focuses on the neurodevelopmental outcome of 4-year-old ART-offspring. STUDY DESIGN, SIZE, DURATION: Longitudinal, prospective follow-up study. PARTICIPANTS, SETTING, METHODS: Four-year-old singletons born to subfertile parents (subfertile group, n = 195), including singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 63), modified natural cycle IVF (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). Data on underlying cause of subfertility and TTP were present. In addition, we assessed newly recruited 4-year-old singletons born to fertile parents after natural conception (reference group, n = 98). Neurological development was evaluated with the neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the occurrence of the clinically relevant form of minor neurological dysfunction (complex MND). The primary outcome was the fluency score, as fluency of movements is easily reduced by subtle brain dysfunction. Data were analysed with univariable and multivariable regression analyses, in which special attention was paid to sex differences in the neurological outcome. MAIN RESULTS AND THE ROLE OF CHANCE: The fluency score, NOS and the prevalence of complex MND were similar in COH-IVF, MNC-IVF and Sub-NC children. The neurological condition of children born to subfertile parents was similar to that of children of fertile parents and was independent of the underlying cause of subfertility. No statistically significant associations were found between TTP and the fluency score and NOS. However, a positive correlation was found between TTP and the prevalence of complex MND (TTP in years, adjusted odds ratio [OR] [95% confidence interval, CI]: 1.207 [1.038 to 1.404], P = 0.014); a correlation which could be attributed to girls, in whom an evident positive correlation was present (adjusted OR [95% CI]: 1.542 [1.161 to 2.047], P = 0.003). A similar association was absent in boys. LIMITATIONS, REASONS FOR CAUTION: The prospective design of our study and small post-natal attrition rate (9.3%) reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception, except for the group of children born to fertile parents, which was newly recruited. The study lacks sufficient power to conclude firmly that increased TTP is associated with a higher prevalence of complex MND. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that the severity of subfertility, rather than its simple presence or components of IVF treatment, affects the neurological outcome. Moreover, girls may be neurologically more vulnerable for the effect of severity of subfertility. The finding that the severity of subfertility may be the decisive factor rather than the presence of a history of subfertility per se corroborates previous reports. Our results cannot be generalized to multiples, as we studied singletons only. STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by the University Medical Center Groningen, grant number: 754510, the Junior Scientific Masterclass, the Postgraduate School Behavioural and Cognitive Neurosciences and the Cornelia Foundation, Groningen, The Netherlands. The authors have no conflicts of interest to declare.

The effect of preimplantation genetic screening on neurological, cognitive and behavioural development in 4-year-old children: follow-up of a RCT.

STUDY QUESTION: Does embryo biopsy inherent to preimplantation genetic screening (PGS) affect neurological, cognitive and behavioural development of 4-year-old children? SUMMARY ANSWER: PGS does not seem to affect neurological, cognitive and behavioural development of 4-year-old singletons; however, our data suggest that it may be associated with altered neurodevelopment in twins. WHAT IS KNOWN ALREADY: Evidence concerning the safety of PGS on neurodevelopmental outcome in offspring is scarce. The present study provides information on neurodevelopmental, cognitive and behavioural outcome of 4-year-old PGS offspring. STUDY DESIGN, SIZE, DURATION: A prospective, assessor-blinded follow-up study of children born to women who participated in a multi-centre RCT on the effect of IVF with or without PGS. PARTICIPANTS/MATERIALS, SETTING, METHODS: At 4 years, 49 children (31 singletons, 9 sets of twins) born following IVF with PGS and 64 children (42 singletons, 11 sets of twins) born following IVF without PGS (controls) were assessed (post-natal attrition 18%). Neurological development was evaluated with the standardized, age-specific and sensitive neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the rate of adverse neurological outcome. Primary outcome was the fluency score, as fluency of movements is easily reduced by subtle dysfunction of the brain. Cognitive development was evaluated with the Kaufman Assessment Battery for Children; behavioural development was evaluated with the Child Behavior Checklist. The effect of PGS was analysed with a mixed effects model. MAIN RESULTS AND THE ROLE OF CHANCE: Based on the intention to treat analysis, neurodevelopmental outcome of PGS children was similar to that of controls. However, additional analyses indicated that PGS affected neurodevelopmental outcome of twins in a different way than that of singletons. The fluency score of singletons born following PGS was similar to that of control singletons [mean values, 95% confidence intervals (CIs): 12.2 (11.5;12.8) and 12.2 (11.6;12.8)], respectively, P = 0.977) that was also true for the other neurodevelopmental parameters. The fluency score of PGS twins was significantly lower than that of control twins [mean values, 95% CIs: 10.6 (9.8;11.3) and 12.3 (11.5;13.1)], respectively, P = 0.001); the same was true for the NOS. In addition, PGS in twins was associated with a higher sequential intelligence quotient score. On the other hand, other neurodevelopmental parameters were similar for PGS twins and control twins. Post hoc sample size calculation for the primary outcome parameter, the fluency score, indicated that the study groups, including the subgroups of singletons and twins, were adequately powered. LIMITATIONS, REASONS FOR CAUTION: We assessed singletons and twins who contributed to the generalizability of the study. A limitation of our study is the relative small size of our study groups and the selective dropout in both groups (dropouts PGS group: higher gestational age; control group: less well-educated parents). These preclude the conclusion that PGS per se is not associated with neurodevelopmental, cognitive and behavioural problems in singletons and the conclusion that PGS is associated with altered neurodevelopmental outcome in twins. WIDER IMPLICATIONS OF THE FINDINGS: The need for careful long-term monitoring of children born following embryo biopsy remains, as it is still applied in the form of PGD and it is still unknown whether embryo biopsy affects long-term neurodevelopmental outcome.

The impact of IVF/ICSI on parental well-being and anxiety 1 year after childbirth.

BACKGROUND: More couples are delaying childbirth resulting in an increase of age-related subfertility in women. Subfertility and assisted reproductive technology (ART) treatments may affect couples' psychological well-being. The aim of the present study was to investigate whether factors related to IVF/ICSI affect anxiety and mental health in couples 1 year after childbirth. METHOD: In this cohort study, we included couples with a singleton pregnancy following IVF/ICSI treatment (n=113) and subfertile couples who naturally conceived (NC; n=83). Parental trait anxiety (Dutch version of the Spielberger State-Trait Anxiety Inventory) and mental health (Dutch version of General Health Questionnaire) were assessed 1 year after childbirth. The influence of fertility-related factors was analyzed with logistic regression analyses. RESULTS: One hundred and ninety-six couples participated, 93% of those eligible. Trait anxiety and mental health were similar in IVF/ICSI and NC groups. However, NC fathers had more often mental health scores in the clinical range (21%) than fathers in the IVF/ICSI group (9%). The risk of having a trait anxiety or mental health score in the clinical range was reduced by the presence of one of the following factors: for females a higher number of IVF/ICSI treatment cycles, and a maternal cause of subfertility, for males having been treated by IVF/ICSI and a longer time to pregnancy. CONCLUSIONS: The present study indicates (i) that IVF/ICSI treatment is not associated with an increase in clinically relevant Spielberger State-Trait Anxiety Inventory and General Health Questionnaire scores in parents 1 year after childbirth and (ii) a higher number of IVF/ICSI treatment cycles and a longer time to pregnancy were associated with less trait anxiety and better mental health. A limitation of the study is the absence of mental health and trait anxiety data at baseline.

The addition of GnRH antagonists in intrauterine insemination cycles with mild ovarian hyperstimulation does not increase live birth rates--a randomized, double-blinded, placebo-controlled trial.

BACKGROUND: This multicenter, double-blinded RCT investigated the efficacy of GnRH antagonists in cycles with mild ovarian hyperstimulation (MOH) followed by IUI in subfertile women. METHODS: Couples diagnosed with unexplained, male factor subfertility or associated with the presence of minimal or mild endometriosis were randomized with a computer-generated list of numbers by a third party in a double-blinded setting to receive either a GnRH antagonists or a placebo in 12 institutional or academic hospitals. All women were treated with recombinant FSH in a low-dose step-up regimen starting on Day 2-4 of the cycle. A GnRH antagonist was added when one or more follicles of 14 mm diameter or more were visualized. When at least one follicle reached a size of ≥18 mm, ovulation was induced by hCG injection. A single IUI was performed 38-40 h later. Couples were offered a maximum of three consecutive cycles. The primary outcome of the trial was live births. Secondary outcomes were pregnancy rates, multiple pregnancy rates, miscarriages and ovarian hyperstimulation syndrome rate. RESULTS: A total of 233 couples were included from January 2006 to February 2009, starting 572 treatment cycles. Live birth rates were not significantly different between the group treated with GnRH antagonist (8.4%; 23/275) and the placebo group (12%; 36/297) (P = 0.30). Three twin pregnancies occurred in the GnRH antagonist group and two twin pregnancies in the placebo group. CONCLUSIONS: Adding a GnRH antagonist in cycles with MOH in an IUI program does not increase live birth rates. Dutch Trial Register no: NTR497.

The Groningen ART cohort study: the effects of ovarian hyperstimulation and the IVF laboratory procedures on neurological condition at 2 years.

BACKGROUND: Up to 4% of children are born following assisted reproduction techniques (ART) yet relatively little is known on neurodevelopmental outcome of these children after 18 months of age. Only a limited number of long-term follow-up studies with adequate methodological quality have been reported. Our aim was to evaluate the effects of ovarian hyperstimulation, IVF laboratory procedures and a history of subfertility on neurological condition at 2 years. METHODS: Singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 66), modified natural cycle IVF (MNC-IVF, n = 56), natural conception in subfertile couples (Sub-NC, n = 87) and in fertile couples (reference group, n = 101) were assessed (using Hempel approach) by neurological examination at 2 years of age. This resulted in a neurological optimality score (NOS), a fluency score and the prevalence of minor neurological dysfunction (MND). Primary outcome was the fluency score, as fluency of movements is easily affected by subtle dysfunction of the nervous system. RESULTS: Fluency score, NOS and prevalence of MND were similar in COH-IVF, MNC-IVF and Sub-NC children. However, the fluency score (P < 0.01) and NOS (P < 0.001) of the three subfertile groups were higher, and the prevalence of MND was lower (P = 0.045), than those in the reference group. CONCLUSIONS: Neurological condition of 2 year olds born after ART is similar to that of children of subfertile couples conceived naturally. Moreover, subfertility does not seem to be associated with a worse neurological outcome. These findings are reassuring, but we have to keep in mind that subtle neurodevelopmental disorders may emerge as children grow older.

Is the birthweight of singletons born after IVF reduced by ovarian stimulation or by IVF laboratory procedures?

Singletons born after IVF are at risk of adverse pregnancy outcome, the cause of which is unknown. The present study investigated the influence of ovarian stimulation and IVF laboratory procedure on birthweight. Birthweight of singleton pregnancies resulting from IVF treatment with (n=161) and without ovarian stimulation (using a modified natural cycle (MNC) protocol; n=158), and spontaneous conceptions in subfertile patients (n=132) were compared. Mean+/-SD birthweight of singletons after conventional IVF with ovarian stimulation, MNC-IVF and natural conception were 3271+/-655, 3472+/-548 and 3527+/-582 g (P=0.001). After adjustment for biological and social confounders, the difference in birthweight between conventional IVF and MNC-IVF was reduced to 88 g and the differences between conventional IVF and MNC-IVF versus spontaneous conceptions to 123 and 23 g, respectively. The results lead to three conclusions. First, a major part of the crude differences in birthweight between the three groups is related to patient and pregnancy characteristics. Second, the IVF laboratory procedure has no influence on birthweight. Third, although a trend towards lower birthweight after ovarian stimulation was found, an adverse effect of ovarian stimulation on birthweight was not substantiated.

The Groningen ART cohort study: ovarian hyperstimulation and the in vitro procedure do not affect neurological outcome in infancy.

BACKGROUND: Due to the growing number of children born following assisted reproduction technology, even subtle changes in the children's health and development are of importance to society at large. The aim of the present study was to evaluate the specific effects of ovarian hyperstimulation and the in vitro procedure on neurological outcome in 4-18-month-old children. METHODS: In this prospective assessor-blinded cohort study, we included singletons born following controlled ovarian hyperstimulation in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) (COH-IVF; n = 68) or modified natural cycle-IVF/ICSI (MNC-IVF; n = 57) or naturally conceived singletons of subfertile couples (NC; n = 90). Children were assessed with standardized, age-specific and sensitive neurological assessments (TINE and Hempel assessment) at 4, 10 and 18 months. Neurological examination resulted in a neurological optimality score (NOS), a fluency score and a clinical neurological classification. Fluency of movements is easily affected by neurological dysfunction and is therefore a sensitive measure for minimal changes in neuromotor development. RESULTS: The NOS and the fluency score were similar in COH-IVF, MNC-IVF and NC children. None of the children showed major neurological dysfunction and rates of minor neurological dysfunction at the three ages were not different between the three conception groups. CONCLUSIONS: We found no effects of ovarian hyperstimulation or the in vitro procedure itself on neurological outcome in children aged 4-18 months. The findings of our study are reassuring, nevertheless it should be kept in mind that subtle neurodevelopmental disorders may emerge when children grow older. Continuation of follow-up in older and larger groups of children is therefore still needed.

The predictive value of ovarian reserve tests for miscarriage in a population of subfertile ovulatory women.

BACKGROUND: The increase in miscarriage rate with female age is attributed to a decline in oocyte quality. This age-related decrease of oocyte quality is accompanied by a decrease in oocyte quantity. Assessment of the number of oocytes by ovarian reserve tests (ORTs) may therefore also represent their quality. The objective of our study was to assess the predictive value of ORTs for miscarriage in subfertile women. METHODS: This study was a subanalysis within a prospective cohort study of 474 subfertile ovulatory couples in two hospitals in Groningen, The Netherlands. The ORTs performed were: antral follicle count (AFC), basal and stimulated levels of follicle-stimulating hormone (FSH) and inhibin B, and the clomiphene citrate challenge test (CCCT). Women who achieved an ongoing pregnancy (n = 233) were compared with women experiencing miscarriage (n = 72) on the results of their ORTs and patient characteristics. RESULTS: In univariate analysis, the outcome of the ORTs did not differ between the groups. Logistic regression analysis including patient characteristics such as female age did not reveal an association between the ORT results and miscarriage either. CONCLUSIONS: Neither AFC, basal and stimulated levels of FSH and inhibin B, nor the CCCT have a statistically significant predictive value for miscarriage in subfertile ovulatory women.

The predictive value of ovarian reserve tests for spontaneous pregnancy in subfertile ovulatory women.

BACKGROUND: The predictive value of ovarian reserve tests (ORTs) for spontaneous pregnancy is unclear. Our study aimed to determine whether ORTs have added value to previously identified prognostic factors for spontaneous pregnancy in subfertile ovulatory couples. METHODS: A prospective cohort study was performed on 474 subfertile ovulatory couples in two hospitals in Groningen, The Netherlands. The ORTs performed were: antral follicle count (AFC), follicle-stimulating hormone (FSH), inhibin B (basal levels and after stimulation with clomiphene citrate) and the clomiphene citrate challenge test. For each couple, the probability of spontaneous pregnancy was retrospectively calculated using the validated Hunault prediction model which includes the main known prognostic factors for spontaneous pregnancy. Outcome measure was time to spontaneous pregnancy resulting in a live birth. RESULTS: When added to the Hunault model, only basal FSH and AFC significantly improved the prediction of spontaneous pregnancy (P-values of 0.05 and 0.04). Absolute changes in predicted probabilities after adding basal FSH or AFC were small: the predicted probability of spontaneous pregnancy shifted >or=10% in only 3.8% and 7.9% of the couples, respectively. CONCLUSIONS: Although basal FSH and AFC significantly improved the validated prediction model for spontaneous pregnancy, the clinical relevance of this finding is limited. We recommend that none of the ORTs studied should be used routinely in the subfertility evaluation of ovulatory couples to predict spontaneous pregnancy chances.

Cumulative pregnancy rates after sequential treatment with modified natural cycle IVF followed by IVF with controlled ovarian stimulation.

BACKGROUND: In modified natural cycle IVF (MNC-IVF), treatment is aimed at using the one follicle that spontaneously develops to dominance, using a GnRH-antagonist together with gonadotrophins in the late follicular phase only. The MNC-IVF is of interest because of its low-risk and patient-friendly profile. The effect of application of MNC-IVF preceding standard IVF with ovarian stimulation on overall results is unknown. METHODS: This single-center cohort study provides follow-up of an earlier study in which nine cycles of MNC-IVF were offered to 268 patients. Ongoing pregnancy rates and live birth rates, as well as time-to-pregnancy after controlled ovarian stimulation-IVF (COS-IVF) following MNC-IVF, were evaluated. RESULTS: Actual observed cumulative ongoing pregnancy rates and live birth rates after sequential treatment with MNC-IVF followed by COS-IVF were 51.5 (95% CI: 45.4-57.6) and 50.0% (95% CI: 43.9-56.1) per patient, of which 8.0 and 6.7% were twins. Median time to ongoing pregnancy was 28.8 weeks. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 56.7% (95% CI: 50.7-62.8). CONCLUSIONS: Sequential treatment with MNC-IVF followed by COS-IVF does not appear to compromise overall success rates, while twin pregnancy rate is low. Because of its patient-friendly and low-risk profile, it seems appropriate to perform MNC-IVF preceding COS-IVF.

[National guideline 'Cryopreservation of ovarian tissue']. / Richtlijn 'Cryopreservatie van ovariumweefsel'.

The treatment of children and young adults with cancer increasingly results in cure, but for a number of female patients this is at the expense of infertility. For women and girls with cancer and the wish to have children in the future, cryopreservation of ovarian tissue may be a solution in the absence of alternatives for the conservation of fertility. Because of the uncertain effectiveness and safety of cryopreservation of ovarian tissue, the Dutch national guideline 'Cryopreservation of ovarian tissue' advises removing and freezing ovarian tissue only if this is done within the framework of scientific research. Reimbursement of this procedure and financing of the relevant and necessary research have not yet been arranged.

Intra-uterine insemination for male subfertility.

BACKGROUND: Intra-uterine insemination (IUI) is one of the most frequently used fertility treatments for couples with male subfertility. Its use, especially when combined with ovarian hyperstimulation (OH) has been subject of discussion. Although the treatment itself is less invasive and expensive than others, its efficacy has not been proven. Furthermore, the adverse effects of OH such as ovarian hyperstimulation syndrome (OHSS ) and multiple pregnancy are a concern. OBJECTIVES: The aim of this review was to determine whether for couples with male subfertility, IUI improves the live birth rates or ongoing pregnancy rates compared with timed intercourse (TI), with or without OH. SEARCH STRATEGY: We searched the Cochrane Menstrual and Disorders Subfertility Group Trials Special Register, the Cochrane Central Register of Controlled Trials (the Cochrane Library, 2006, issue 3), MEDLINE (1966 to May 2006), EMBASE (1980 to May 2006), SCIsearch and the reference lists of articles. We hand searched abstracts of the American Society for Reproductive Medicine, the European Society for Human Reproduction and Embryology. Authors of identified articles were contacted for unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCT's) with at least one of the following comparisons were included: 1) IUI versus TI or expectant management both in natural cycles 2) IUI versus TI both in cycles with OH 3) IUI in natural cycles versus TI + OH 4) IUI + OH versus TI in natural cycles 5) IUI in natural cycles versus IUI + OH. Couples with abnormal sperm parameters only were included. DATA COLLECTION AND ANALYSIS: Two co-reviewers independently performed quality assessment and data extraction. Where possible data were pooled, and a meta-analysis was performed. Sensitivity and subgroup analyses were carried out where possible and appropriate. MAIN RESULTS: Three trials of parallel design, and five trials of cross-over design with pre-cross-over data were included in the meta-analysis. Three compared IUI with TI both in stimulated cycles. The remaining four of these studies compared IUI versus IUI + OH . Three studies reported on our main outcome of interest live birth rate per couple. For the comparison IUI versus TI both in natural cycles no evidence of difference between the probabilities of pregnancy rates per woman after IUI compared with TI was found (Peto OR 5.3, 95% CI 0.42 to 67). No statistically significant of difference between pregnancy rates (PR) per couple for IUI + OH versus IUI could be found (Peto OR 1.47, 95% CI 0.92 to 2.37). For the comparison IUI versus TI both in stimulated cycles there was no evidence of statistically significant difference in pregnancy rates per couple either (Peto OR 1.67, 95% CI 0.83 to 3.37). There were insufficient data available for adverse outcomes such as OHSS, multiple pregnancy, miscarriage rate and ectopic pregnancy to perform a statistical analysis. For the other two comparisons no RCT's were found which reported pregnancy rates per couple. A further 10 studies which included one of the comparisons of interests were found. Since these studies reported pregnancy rates per cycle only these data could not be included in the meta-analysis. AUTHORS' CONCLUSIONS: There was insufficient evidence of effectiveness to recommend or advise against IUI with or without OH above TI, or vice versa. Large, high quality randomised controlled trials, comparing IUI with or without OH with pregnancy rate per couple as the main outcome of interest are lacking. There is a need for such trials since firm conclusions cannot be drawn yet.

Semen preparation techniques for intrauterine insemination.

BACKGROUND: Semen preparation techniques for assisted reproduction, including intrauterine insemination (IUI), were developed to separate the motile morphological normal spermatozoa. Leucocytes, bacteria and dead spermatozoa produce oxygen radicals that negatively influence the ability to fertilize the egg. The yield of as many motile, morphologically normal spermatozoa as possible might influence treatment choices and therefore outcomes. OBJECTIVES: To compare the effectiveness of gradient, swim-up, or wash and centrifugation semen preparation techniques on clinical outcome in subfertile couples undergoing intrauterine insemination (IUI). SEARCH STRATEGY: We searched the Menstrual Disorders and Subfertility Group Trials Register (13 January 2007), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 2), MEDLINE (1966 to January 2007 ), EMBASE (1980 to January 2007), Science Direct Database (1966 to January 2007), National Research Register (2000 to 2007), Biological Abstracts (2000 to January 2007), CINAHL (1982 to October 2006) and reference lists of relevant articles. We also contacted experts and authors in the field. SELECTION CRITERIA: Parallel randomized controlled trials (RCTs) comparing the efficacy of semen preparation techniques used for subfertile couples undergoing IUI in terms of clinical outcome were included. DATA COLLECTION AND ANALYSIS: Two reviewer authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Five RCTs, including 262 couples in total, were included in the meta-analysis (Dodson 1998; Grigoriou 2005; Posada 2005; Soliman 2005; Xu 2000). Xu compared the three techniques; Soliman compared a gradient technique versus a wash technique; Dodson and Posada compared a gradient technique versus a swim-up technique; whereas Grigoriou compared swim-up versus a wash technique. No trials reported the primary outcome of live birth. There was no evidence of a difference between pregnancy rates (PR) for swim-up versus a gradient or wash and centrifugation technique (Peto OR 1.57, 95% CI 0.74 to 3.32; Peto OR 0.41, 95% CI 0.15 to 1.10, respectively); nor in the two studies comparing a gradient technique versus wash and centrifugation (Peto OR 1.76, 95% CI 0.57 to 5.44). There was no evidence of a difference in the miscarriage rate (MR) in two studies comparing swim-up versus a gradient technique (Peto OR 0.13, 95% CI 0.01 to 1.33). AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend any specific preparation technique. Large high quality randomised controlled trials, comparing the effectiveness of a gradient and/ or a swim-up and/ or wash and centrifugation technique on clinical outcome are lacking. Further randomised trials are warranted.

Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility.

BACKGROUND: Intrauterine insemination (IUI) combined with ovarian hyperstimulation (OH) has been demonstrated to be an effective form of treatment for subfertile couples. Several ovarian stimulation protocols combined with IUI have been proposed, but it is still not clear which stimulation protocol and which dose is the most cost-effective. OBJECTIVES: To evaluate ovarian stimulation protocols for intrauterine insemination for all indications. SEARCH STRATEGY: We searched for all publications which described randomised controlled trials comparing different ovarian stimulation protocols followed by IUI. We searched the Menstrual Disorders and Subfertility Group's Central register of Controlled Trials (CENTRAL). We searched the electronic databases of MEDLINE (January 1966 to present) and EMBASE (1980 to present). SELECTION CRITERIA: Randomised controlled trials only were considered for inclusion in this review. Trials comparing different ovarian stimulation protocols combined with IUI were selected and reviewed in detail. DATA COLLECTION AND ANALYSIS: Two independent review authors independently assess trial quality and extracted data. MAIN RESULTS: Forty three trials involving 3957 women were included. There were 11 comparisons in this review. Pregnancy rates are reported here since results of live birth rates were lacking. Seven studies (n = 556) were pooled comparing gonadotrophins with anti-oestrogens showing significant higher pregnancy rates with gonadotrophins (OR 1.8, 95% CI 1.2 to 2.7). Five studies (n = 313) compared anti-oestrogens with aromatase inhibitors reporting no significant difference (OR 1.2 95% CI 0.64 to 2.1). The same could be concluded comparing different types of gonadotrophins (9 studies included, n = 576). Four studies (n = 391) reported the effect of adding a GnRH agonist which did not improve pregnancy rates (OR 0.98 95% CI 0.6 to 1.6), although it resulted in significant higher multiple pregnancy rates (OR 2.9 95% CI 1.0 to 8). Data of three studies (n = 299) showed no convincing evidence of adding a GnRH antagonist to gonadotrophins (OR 1.5 95% CI 0.83 to 2.8). The results of two studies (n = 297) reported no evidence of benefit in doubling the dose of gonadotrophins (OR 1.2 95% 0.67 to 1.9) although the multiple pregnancy rates and OHSS rates were increased. For the remaining five comparisons only one or none studies were included. AUTHORS' CONCLUSIONS: Robust evidence is lacking but based on the available results gonadotrophins might be the most effective drugs when IUI is combined with ovarian hyperstimulation. When gonadotrophins are applied it might be done on a daily basis. When gonadotrophins are used for ovarian stimulation low dose protocols are advised since pregnancy rates do not differ from pregnancy rates which result from high dose regimen, whereas the chances to encounter negative effects from ovarian stimulation such as multiples and OHSS are limited with low dose gonadotrophins. Further research is needed for each comparison made.

Intra-uterine insemination for male subfertility.

BACKGROUND: Intra-uterine insemination (IUI) is one of the most frequently used fertility treatments for couples with male subfertility. Its use, especially when combined with ovarian hyperstimulation (OH) has been subject of discussion. Although the treatment itself is less invasive and expensive than others, its efficacy has not been proven. Furthermore, the adverse effects of OH such as ovarian hyperstimulation syndrome (OHSS ) and multiple pregnancy are a concern. OBJECTIVES: The aim of this review is to determine whether for couples with male subfertility, IUI improves the live birth rates or ongoing pregnancy rates compared with timed intercourse (TI), with or without OH. SEARCH STRATEGY: We searched the Cochrane Menstrual and Disorders Subfertility Group Trials Special Register, the Cochrane Central Register of Controlled Trials (the Cochrane Library, 2006, issue 3), MEDLINE (1966 to May 2006), EMBASE (1980 to May 2006), SCIsearch and the reference lists of articles. We hand searched abstracts of the American Society for Reproductive Medicine, the European Society for Human Reproduction and Embryology. Authors of identified articles were contacted for unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCT's) with at least one of the following comparisons were included: 1) IUI versus TI or expectant management both in natural cycles 2) IUI versus TI both in cycles with OH 3) IUI in natural cycles versus TI + OH 4) IUI + OH versus TI in natural cycles 5) IUI in natural cycles versus IUI + OH Couples with abnormal sperm parameters only were included. DATA COLLECTION AND ANALYSIS: Two co-reviewers independently performed quality assessment and data extraction. Where possible data were pooled, and a meta-analysis was performed. Sensitivity and subgroup analyses were carried out where possible and appropriate. MAIN RESULTS: Three trials of parallel design, and five trials of cross-over design with pre-cross-over data were included in the meta-analysis. Three compared IUI with TI both in stimulated cycles. The remaining four of these studies compared IUI versus IUI + OH . Three studies reported on our main outcome of interest live birth rate per couple. For the comparison IUI versus TI both in natural cycles no evidence of difference between the probabilities of pregnancy rates per woman after IUI compared with TI was found (Peto OR 5.3, 95% CI 0.42 to 67). No statistically significant of difference between pregnancy rates (PR) per couple for IUI + OH versus IUI could be found (Peto OR 1.47, 95% CI 0.92 to 2.37). For the comparison IUI versus TI both in stimulated cycles there was no evidence of statistically significant difference in pregnancy rates per couple either (Peto OR 1.67, 95% CI 0.83 to 3.37). There were insufficient data available for adverse outcomes such as OHSS, multiple pregnancy, miscarriage rate and ectopic pregnancy to perform a statistical analysis. For the other two comparisons no RCT's were found which reported pregnancy rates per couple. A further 10 studies which included one of the comparisons of interests were found. Since these studies reported pregnancy rates per cycle only these data could not be included in the meta-analysis. AUTHORS' CONCLUSIONS: There was insufficient evidence of effectiveness to recommend or advise against IUI with or without OH above TI, or vice versa. Large, high quality randomised controlled trials, comparing IUI with or without OH with pregnancy rate per couple as the main outcome of interest are lacking. There is a need for such trials since firm conclusions cannot be drawn yet.

Monocyte activation, but not granulocyte activation, is inhibited in the presence of developing ovarian follicles.

This study was set up to evaluate the influence of ovarian factors on the acute phase of the endotoxin-induced glomerular inflammatory reaction. Six groups of rats with permanent jugular vein cannulas were used. This included three groups with increased progesterone and/or 17beta-oestradiol concentrations (day 14 pregnant rats, pseudopregnant rats and lactating rats), one group with the presence of developing ovarian follicles (cyclic rats), and two groups with both increased sex hormone concentrations and the presence of developing ovarian follicles (day 14 pregnant rats treated with FSH and day 21 pregnant rats). Rats were infused for 1h with either saline or endotoxin (1 microg/kg body weight) and sacrificed 4h after the infusion. Kidney sections were snap-frozen and prepared for immunohistochemistry. Endotoxin-induced glomerular granulocyte infiltration was increased only in the groups of rats with increased progesterone and/or 17beta-oestradiol concentrations. This could be due to endotoxin-induced ICAM-1 and/or VCAM-1 expression, which was observed in all endotoxin-treated groups and in all endotoxin-treated groups with increased sex hormone concentrations, respectively. It could also be due to an effect on granulocytes per se, since the number of endotoxin-induced CD11b-positive cells in the glomeruli was increased only in the groups with increased sex hormone concentrations. Endotoxin-induced glomerular monocyte infiltration, however, was seen only in those groups in which developing ovarian follicles were lacking (i.e. day 14 pregnant, pseudopregnant and lactating rats), suggesting that developing ovarian follicles produce anti-inflammatory factors. These factors did not have an effect on endothelial or leukocyte adhesion molecule expression. We hypothesize that the presence of elevated progesterone concentrations increased the endotoxin-induced glomerular granulocyte infiltration, while endotoxin-induced glomerular monocyte infiltration was inhibited in the presence of developing ovarian follicles.