Intrauterine Insemination Treatment Research Articles

O-202 Novel use of hyaluronan enriched media for improving implantation in intrauterine insemination: a prospective randomised controlled trial (HEMI Trial)

Abstract Study question Does the intrauterine instillation of hyaluronan-enriched media influence the implantation rate and reproductive outcomes in patients undergoing controlled ovarian stimulation and intrauterine insemination? Summary answer The intrauterine instillation of Hyaluronan-enriched media significantly improved the implantation rates and ongoing pregnancy rate in women undergoing controlled ovarian stimulation and intrauterine insemination treatment What is known already Hyaluronan is a macromolecule belonging to the glycosaminoglycans family, secreted by cumulus granulosa cells, and is naturally present in the female reproductive tract. Various mechanisms have been proposed to explain the implantation-enhancing properties of Hyaluronan including increased cell-cell and cell-matrix adhesion, by producing a viscous environment for the integration of embryo in intrauterine fluid and its autocrine and paracrine functions via CD44 receptors. This is probably the first trial studying the effect of hyaluronan-enriched media in intrauterine insemination treatment. The proposed novel intervention is based on the biological plausibility and proven safety of hyaluronan in IVF studies. Study design, size, duration This parallel group Randomised Controlled trial was conducted over 2 years of duration, from 2021 to 2023. A total of 100 couples diagnosed with unexplained infertility planned for controlled ovarian stimulation and intrauterine insemination (COS-IUI) treatment were randomized into the intervention and control arm of the trial. Before the commencement of the study, the trial was registered with the Clinical Trial Registry-India (CTRI), and institutional ethical approval was obtained. Participants/materials, setting, methods 100 couples diagnosed with unexplained infertility attending tertiary-level university hospital were allocated to the intervention and control group using block randomization in 1:1 allocation. In the intervention group, the participants underwent intrauterine instillation of 0.4 ml of hyaluronan enriched media, 4 days following intrauterine insemination treatment. The statistical package SPSS (version 21) was used for analysis and results were considered to be statistically significant if the P-value was <0.05. Main results and the role of chance The mean female age of the study population was 28.12±3.74 years with an average duration of infertility of 3.95 ±2.17 years. The study participants underwent an average of 1.7 IUI cycles in the control group and 1.6 cycles in the intervention group. A cumulative biochemical pregnancy rate of 36.5% and 16.6% was observed amid the the intervention group and control group respectively and the difference was statistically significant with a p-value of 0.039. Similarly, the cumulative ongoing pregnancy rate beyond 20 weeks of gestation was statistically significantly higher among the intervention arm of the trial as compared to the control group (31.7% vs 11.9%, p = 0.035). There was a trend of improved clinical pregnancy rate among the intervention participants, however, this difference did not reach statistical significance (34.1% vs 16.6%, p = 0.067). The miscarriage rate was comparable among both groups. The number needed to treat was estimated to be 5, which in effect meant that 5 women would have to receive intrauterine instillation of hyaluronan enriched media for 1 additional ongoing pregnancy. Limitations, reasons for caution The longer follow-up period would have allowed the reporting of live-birth rate which is undeniably the most meaningful parameter to appraise an intervention. Larger multicentric studies are required to establish the clinical benefit and generalisability of the proposed intervention. Wider implications of the findings The study proposes a potential novel, simple, minimally invasive, and patient-acceptable intervention to increase the success rates of intrauterine insemination. Being the first study on the topic, the study can provide a basis for future large multicentric studies on the topic. Trial registration number Clinical Trial Registry-India (CTRI) number- CTRI/2021/10/037064.

Optimizing intrauterine insemination: A systematic review and meta-analysis of the effectiveness and safety of clinical treatment add-ons.

Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add-on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta-analysis is to assess the effectiveness and safety of add-on interventions to the standard IUI protocol and to provide evidence-based recommendations on techniques used to optimize the clinical outcomes of IUI treatment. Systematic review and meta-analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner's or donor sperm. A meta-analysis based on random effects was performed for each outcome and add-on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857. Sixty-six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09-1.72, I2 = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03-2.01, I2 = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00-1.94, I2 = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions. The findings of this systematic review and meta-analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add-ons could benefit specific patient groups.

Development of a machine learning-based prediction model for clinical pregnancy of intrauterine insemination in a large Chinese population.

This study aimed to evaluate the effectiveness of a random forest (RF) model in predicting clinical pregnancy outcomes from intrauterine insemination (IUI) and identifying significant factors affecting IUI pregnancy in a large Chinese population. RESULTS: A total of 11 variables, including eight from female (age, body mass index, duration of infertility, prior miscarriage, and spontaneous abortion), hormone levels (anti-Müllerian hormone, follicle-stimulating hormone, luteinizing hormone), and three from male (smoking, semen volume, and sperm concentration), were identified as the significant variables associated with IUI clinical pregnancy in our Chinese dataset. The RF-based prediction model presents an area under the receiver operating characteristic curve (AUC) of 0.716 (95% confidence interval, 0.6914-0.7406), an accuracy rate of 0.6081, a sensitivity rate of 0.7113, and a specificity rate of 0.505. Importance analysis indicated that semen volume was the most vital variable in predicting IUI clinical pregnancy. The machine learning-based IUI clinical pregnancy prediction model showed a promising predictive efficacy that could provide a potent tool to guide selecting targeted infertile couples beneficial from IUI treatment, and also identify which parameters are most relevant in IUI clinical pregnancy.

Effects of male hepatitis B virus infection and serostatus on sperm quality, pregnancy outcomes, and neonatal outcomes following intrauterine insemination.

To evaluate the impact of male hepatitis B virus (HBV) infection and serostatus on sperm quality, pregnancy outcomes, and neonatal outcomes following intrauterine insemination for infertility. We retrospectively analyzed data from 962 infertile couples undergoing intrauterine insemination treatment at a single center. The case group comprised 212 infertile couples with male HBV infection, and the control group comprised 750 noninfected infertile couples. The couples were further divided into subgroups according to their hepatitis B e antigen (HBeAg)/anti-HBe status: hepatitis B surface antigen (HBsAg)+HBeAg- (group A), HBsAg+HBeAg+ (group B), and HBsAg-HBeAg- (control group). The main outcome parameters, including the seminal parameters, clinical pregnancy rate, miscarriage rate, live birth rate, preterm delivery rate, multiple pregnancy rate, delivery type, birth weight, and sex ratio, were compared. A lower sperm acrosin activity, higher cesarean rate, and newborn sex ratio were observed in the HBV-infected group and group A in comparison with the control group (P < 0.05). However, the standard sperm parameters, clinical pregnancy rate, miscarriage rate, live birth rate, preterm delivery, and birth weight showed no statistically significant differences among the groups. Male HBV infection does not adversely impact standard sperm parameters or pregnancy outcomes but can influence sperm acrosin activity and some neonatal outcomes. Moreover, the effect may vary among different HBV serostatuses.

The impact of thyroid autoimmunity on pregnancy outcomes in women with unexplained infertility undergoing intrauterine insemination: a retrospective single-center cohort study and meta-analysis.

Infertility affects 8-12% of couples worldwide, with 15-30% classified as unexplained infertility (UI). Thyroid autoimmunity (TAI), the most common autoimmune disorder in women of reproductive age, may impact fertility and pregnancy outcomes. However, the underlying mechanism is unclear. This study focuses on intrauterine insemination (IUI) and its potential association with TAI in UI patients. It is the first meta-analysis following a comprehensive literature review to improve result accuracy and reliability. Retrospective cohort study analyzing 225 women with unexplained infertility, encompassing 542 cycles of IUI treatment. Participants were categorized into TAI+ group (N=47, N= 120 cycles) and TAI- group (N=178, N= 422 cycles). Additionally, a systematic review and meta-analyses following PRISMA guidelines were conducted, incorporating this study and two others up to June 2023, totaling 3428 IUI cycles. Analysis revealed no significant difference in independent variables affecting reproductive outcomes. However, comparison based on TAI status showed significantly lower clinical pregnancy rates (OR: 0.43, P= 0.028, 95%CI: 0.20-0.93) and live birth rate (OR: 0.20, P= 0.014, 95%CI: 0.05 ~ 0.71) were significantly lower than TAI- group. There was no significant difference in pregnancy rate between the two groups (OR: 0.61, P= 0.135, 95%CI: 0.32-1.17). However, the meta-analysis combining these findings across studies did not show statistically significant differences in clinical pregnancy rates (OR:0.77, P=0.18, 95%CI: 0.53-1.13) or live birth rates (OR: 0.68, P=0.64, 95%CI: 0.13-3.47) between the TAI+ and TAI- groups. Our retrospective cohort study found an association between TAI and reduced reproductive outcomes in women undergoing IUI for unexplained infertility. However, the meta-analysis incorporating other studies did not yield statistically significant associations. Caution is required in interpreting the relationship between thyroid autoimmunity and reproductive outcomes. Future studies should consider a broader population and a more rigorous study design to validate these findings. Clinicians dealing with women with unexplained infertility and TAI should be aware of the complexity of this field and the limitations of available evidence.

Effect of follicle size on pregnancy outcomes in patients undergoing first letrozole-intrauterine insemination.

Letrozole has been proven to be an effective method for inducing ovulation. However, littleattentionhasbeenpaidto whether the lead follicle size will affect the success rate of intrauterine insemination (IUI) with ovulation induction with alone letrozole. Therefore, we hope to investigate the effect of dominant follicle size on pregnancy outcomes on human chorionic gonadotropin (hCG) day of the first letrozole-IUI. A retrospective cohort study design was employed. We included patients with anovulation or unexplained infertility undergoing first IUI treatment with letrozole for ovarian stimulation. According to the dominantfolliclesize measured on the day of hCG trigger, patients were divided into six groups (≤ 18mm, 18.1-19.0mm, 19.1-20.0mm, 20.1-21.0mm, 21.1-22.0mm, > 22mm). Logistic models were used for estimating the odds ratios (ORs) with their 95% confidence interval (CIs) for achieving aclinicalpregnancyor alivebirth. A restricted cubic spline was drawn to explore the nonlinear relationship between follicle size and IUI outcomes. A total of 763 patients underwent first letrozole-IUI cycles in our study. Fisherexact test showed significant differences among the six follicle-size groups in the rates of pregnancy, clinical pregnancy and live birth (P < 0.05 in each group). After adjusting the potential confounding factors, compared with the follicles ≤ 18mm in diameter group, 19.1-20.0mm, 20.1-21.0mm groups were 2.3 or 2.56 times more likely to get live birth [adjusted OR = 2.34, 95%CI (1.25-4.39); adjusted OR = 2.56, 95% CI (1.30-5.06)]. A restricted cubic spline showed an invertedU-shaped relationship between the size of dominant follicles and pregnancy rate, clinical pregnancy rate, and live birth rate, and the optimal follicle size range on the day of hCG trigger was 19.1-21.0mm. When the E2 level on the day of hCG trigger was low than 200pg/mL, the clinical pregnancy rates of 19.1-20.0mm, 20.1-21.0mm groups were still the highest. The optimal dominant follicle size was between 19.1 and 21.0mm in hCG-triggered letrozole-IUI cycles. Either too large or too small follicles may lead to a decrease in pregnancy rate. Using follicle size as a predicator of pregnancy outcomes is more meaningful when estrogen on the day of hCG trigger is less than 200pg/ml.

Assessment of clinical pregnancies in up to eight ovarian stimulation with intrauterine insemination treatment cycles in those unable to proceed with in vitro fertilization

To study the primary objective of clinical pregnancy (CP) rate per ovarian stimulation with intrauterine insemination (OS-IUI) treatment cycle in patients with repetitive cycles up to a maximum of 8 cycles. Retrospective cohort. Large fertility clinic. A total of 37,565 consecutive OS-IUI cycles from 18,509 patients were included in this study. Those with anovulatory diagnoses, tubal factor infertility, male factor infertility, using donor sperm, canceled cycles, and those with missing data for either baseline characteristics or outcome were excluded. The CP rate was analyzed using generalized estimating equations and controlled for age, stimulation protocol, and body mass index. Clinical pregnancy was defined as intrauterine gestation with fetal heartbeat visible on ultrasound. A total of 37,565 consecutive OS-IUI cycles from 2002 through 2019 at a private practice facility were evaluated. All cycles met inclusion criteria and were used in generalized estimating equation modeling. Patients aged <35 years comprised 47.6% of the cohort. After adjustment for confounders, the mean predicted probability of CP for cycles one to 8 was 15.7% per cycle. The mean predicted probability of CP in aggregated data from cycles 2 to 4 was only 1.7% lower compared with cycle 1 as the referent (16.7% vs. 15.0%, 95% confidence interval [CI] 2nd: 0.88 {0.82, 0.95}, 3rd: 0.86 {0.79, 0.93}, 4th: 0.88 {0.79, 0.98}). However, the 15.0% mean predicted probability of CP for the second through the fourth cycle was concordant with the mean for all included cycles (15.7%). The mean predicted probability of CP of cycles 5 to 8 was not significantly different compared with the referent (16.7% vs. 16.1%, 95% CI 5th: 0.97 [0.85, 1.11], 6th: 0.93 [0.79, 1.10], 7th: 1.01 [0.81, 1.26], 8th: 1.01 [0.76, 1.34]). The modeling of consecutive cycles suggested that the adjusted cumulative predicted probability of CP from OS-IUI continues to increase with each of the 8 successive cycles. Clinical pregnancy rates are satisfactory in up to 8 consecutive OS-IUI treatment cycles. These data are useful for counseling, especially in those patients for whom invitro fertilization is not financially or ethically feasible.

SPERM PARAMETERS' PREDICTIVE VALUE IN INTRAUTERINE INSEMINATION SUCCESS: A SINGLE-CENTER EXPERIENCE

Although intrauterine insemination is a widely used assisted reproductive technique there is no consensus on sperm parameters that affect the probability of pregnancy. Therefore, the purpose of this study was to determine whether semen parameters affect intrauterine insemination success. A total of 403 couples (345 negative pregnancies, and 58 positive pregnancy) that underwent 549 intrauterine insemination treatment cycles for heterogenous indications were included in the study. Clomiphen citrate, letrazole and/or gonadotropins were used for ovarian stimulation in women in this study. The spermiogram tests of the spouse of receiving IUI tretment were examined. Clinical pregnancy occurred in 58 of 549 intrauterine insemination (10.56%). Unexplained infertility, polycystic ovary syndrome, and cervical-tubal factors were higher in positive pregnancy group compared to negative pregnancy group while male factor was more prevalant in negative pregnancy group comparison to positive pregnancy group (p=0.03). There was no statistical difference between women with positive and negative pregnancy in terms of age (≤ 35 and &gt; 35), body mass index, infertility type, infertility time, endometrial thickness on HCG day, stimulation protocol, cycle numbers, number of insemination, estradiol, prolactin, LH, FSH, and TSH levels (p&gt;0.05). The sperm characteristics in males [ejaculate volum, sperm concentration, total sperm count, motility, immotility, and total progressive motile sperm count] did not significantly differed between positive and negative pregnancy groups (p&gt;0.05).&#x0D; Briefly, the present study found that the conception probability of intrauterine insemination did not correlate with the spermiogram parameters.

Effect of female body mass index on intrauterine insemination outcomes: a systematic review and meta-analysis

The prevalence of women with a raised body mass index (BMI) seeking assisted conception treatment is increasing. Findings of existing studies evaluating the effect of female BMI on intrauterine insemination (IUI) treatment outcomes remain inconsistent. This systematic review and meta-analysis evaluate the effect of female BMI on IUI treatment outcomes. Two authors independently conducted data extraction and assessed study quality. Risk ratios (RR) and 95% confidence intervals were calculated using the Mantel-Haenszel approach for dichotomous outcomes. 11 studies involving 23,145 IUI treatment events, comprising 21,211 cycles from 8 studies, and 1,934 participants in three studies, met the inclusion criteria for the meta-analysis. Two cohorts of women undergoing IUI treatment were compared - women with normal BMI < 25 kg/m2 were compared with a second cohort of women with a BMI category ≥ 25 kg/m2. There was no statistically significant difference in live birth rate (LBR) (RR 1.06, 95% CI 0.86–1.307); clinical pregnancy rate (CPR) (RR 0.94, 95% CI 0.78–1.13); miscarriage (RR 0.92, 95% CI 0.31–2.74) or ectopic pregnancy rate (RR 2.20, 95% CI 0.78–6.23). Our meta-analysis showed that a raised female BMI did not affect IUI treatment outcomes. Nevertheless, weight loss counselling should be offered to women with a raised BMI undergoing IUI, to reduce the associated obstetric morbidity.

Should IUI replace IVF as first-line treatment for unexplained infertility? A literature review

BackgroundUnexplained infertility accounts for 25% of infertility causes in the UK. Active intervention methods, such as intrauterine insemination (IUI) or in vitro fertilisation (IVF), are often sought. Despite the National Institute for Health and Care Excellence (NICE) recommending IVF for unexplained infertility, this recommendation has generated an ongoing debate, with few fertility clinics discontinuing the use of IUI as the first-line management of choice. In contrast to NICE, recent guidance released from the European Society for Human Reproduction and Embryology (ESHRE) in August 2023 supports the use of IUI as first-line. High-quality evidence behind such interventions is lacking, with current literature providing conflicting results.AimsThis review aims to provide a literature overview exploring whether IUI or IVF should be used as first-line treatment for couples with unexplained infertility, in the context of current guidelines.MethodsThe primary outcome used to assess efficacy of both treatment methods is live birth (LB) rates. Secondary outcomes used are clinical pregnancy (CP) and ongoing pregnancy (OP) rates. A comprehensive literature search of 4 databases: Ovid MEDLINE, EMBASE, Maternity & Infant Care and the Cochrane Library were searched in January 2022. Upon removal of duplications, abstract screening, and full-text screening, a total of 34 papers were selected.Discussion/conclusionThis review highlights a large discrepancy in the literature when examining pregnancy outcomes of IUI and IVF treatments. Evidence shows IUI increases LB and CP rates 3-fold compared to expectant management. Literature comparing IUI to IVF is less certain. The review finds the literature implies IVF should be used for first-line management but the paucity of high-quality randomised controlled trials (RCTs), coupled with heterogeneity of the identified studies and a lack of research amongst women > 40 years warrants the need for further large RCTs. The decision to offer IUI with ovarian stimulation (IUI-OS) or IVF should be based upon patient prognostic factors. We suggest that IUI-OS could be offered as first-line treatment for unexplained infertility for women < 38 years, with good prognosis, and IVF could be offered first to those > 38 years. Patients should be appropriately counselled to enable informed decision making.

Pregnancy outcomes of intrauterine insemination in young patients with diminished ovarian reserve: a multicenter cohort study

BackgroundTo date, there is no consensus on whether intrauterine insemination (IUI) treatment is required in young patients with diminished ovarian reserve (DOR). Pregnancy outcomes in young DOR patients undergoing IUI are controversial. The existing studies are all single-center studies, with no existing multicenter cohort studies. The purpose of this multicenter study was to investigate the pregnancy outcomes of young DOR patients undergoing IUI.MethodsThis multicenter cohort study included a total of 4600 cycles in 2204 infertile patients who underwent IUI treatment in three reproductive medical centers between September 2018 and January 2022. The research subjects were divided into two groups according to their serum anti-Müllerian hormone (AMH) levels. Propensity score matching (PSM) was used to match the research subjects at a ratio of 1:4. The pregnancy outcomes in the two groups were compared.ResultsThere was no significant difference in the clinical pregnancy rates (CPR), biochemical rates, and ectopic pregnancy rates between the two groups (P > 0.05). There were, however, significant differences in the miscarriage rates between the groups (P < 0.05). The live birth rates (LBR) were 6.6 vs. 9.9 between the two groups. The multivariable logistic regression models reveal that body mass index, AMH were significantly correlated with CPR; AMH were significantly correlated with LBR; BMI, follicle stimulating hormone were significantly correlated with miscarriage rate.ConclusionsThe clinical pregnancy rate of DOR patients was not significantly different from that of NOR patients; however, the miscarriage rates were significantly different from those of NOR patients.

SUMO1 and Defective Spermatozoa Correlate with Endogenous Hydrogen Peroxide and Live Birth Outcome in Intrauterine Insemination Cycles for Unexplained Infertility.

This study aimed to investigate the correlation between hydrogen peroxide (H2O2), small ubiquitin-like modifier molecules (SUMO), and pregnancy outcomes in couples with unexplained infertility (UI) undergoing intrauterine insemination (IUI) treatment. We prospectively collected semen samples from 56 couples with UI and divided the spermatozoa into motile and immotile fractions by density gradient centrifugation (DSC). Immunofluorescence staining was used to examine the immunostaining and localization of nuclear pore complex (NPC), SUMO1, and SUMO2/3 in spermatozoa. We detected H2O2 levels by chemiluminescence methods. We found that H2O2 levels correlated with NPC (neck) (r = 0.400) and NPC (tail) (r = 0.473) in motile sperm fractions. In immotile fractions, H2O2 positively correlated with NPC (tail) (r = 0.431) and SUMO1 (neck) (r = 0.282). Furthermore, the positive NPC (tail) group had a significantly lower live birth rate than the negative NPC group (17.9% = 5/28 vs. 42.9% = 12/28). In conclusion, H2O2 positively correlated with SUMO1 (neck) and NPC (tail) in human spermatozoa. The DSC may partially eliminate defective spermatozoa (positive NPC staining); however, if defective spermatozoa remain in the motile fraction, this scenario is associated with a low live birth rate following IUI treatment.

Pregnancy among Women Undergoing Intrauterine Insemination in a Centre.

Intrauterine insemination is often performed as the first-line treatment option in many subfertility cases. Successful intrauterine insemination treatment among indicated couples helps to reduce unnecessary in-vitro fertilisation treatment. Although widely practised, the data on pregnancy after intrauterine insemination treatment is limited. The aim of this study was to find out the prevalence of pregnancy among women undergoing intrauterine insemination in a centre. A descriptive cross-sectional study was conducted at a centre among women undergoing intrauterine insemination. Data from 15 May 2017 to 15 April 2021 were collected between 16 June 2022 to 1 July 2022 from the hospital records. Ethical approval was taken from the Nepal Health Research Council. Systematic sampling technique was applied to select the appropriate sample. The point estimate was calculated at a 95% Confidence Interval. Among 225 women undergoing intrauterine insemination, pregnancy was achieved in 23 (10.22%) (6.26-14.18, 95% Confidence Interval). The mean age of pregnant women was 29.17±3.34 years and the mean duration of infertility was 3.93±2.90 years. More than half of the pregnant women 13 (56.52%) had undergone insemination with the husband's semen whereas the remaining 10 women (43.48%) had undergone insemination with donor semen. The prevalence of pregnancy among women undergoing intrauterine insemination was similar to other studies done in similar settings. artificial insemination; Nepal; pregnancy rate.

Review of Intrauterine insemination (IUI) treatment factors and influence on the success rates

Review of Intrauterine insemination (IUI) treatment factors and influence on the success rates

P-789 Unexplained subfertility in women aged 38 years and above: could intrauterine insemination be an alternative for in vitro fertilization? A systematic review and meta-analysis

Abstract Study question Considering current available evidence, how do intrauterine insemination and IVF compare in terms of pregnancy outcomes in women aged &amp;gt; 38 years with unexplained subfertility? Summary answer In women &amp;gt; 38 years both IUI and IVF lead to pregnancies and live births, there is insufficient evidence to determine the relative effectiveness What is known already Solid evidence has shown that intrauterine insemination (IUI) with ovarian stimulation (OS) is the preferred treatment option for women with unexplained subfertility below the age of 38. In women who are 38 or older IVF is the first choice of treatment, according to the Dutch guideline in order to "not waste any more time” Evidence of IVF being more effective compared to IUI-OS is lacking while IVF compared to IUI-OS is an invasive, costly and burdensome procedure. Study design, size, duration We have conducted a systematic review and meta-analysis after a comprehensive literature search which includes articles on IVF, IUI, and both, from May 1985 to May 2022. We have included randomized controlled trials and cohort studies regarding IUI and/or IVF treatment in women aged 38 and above with unexplained subfertility and/or mild subfertility factors. Participants/materials, setting, methods The primary outcome was live birth rate and primary safety outcome was miscarriage rate. Data of the comparative IUI versus IVF studies were pooled in a forest plot and expressed in risk ratio with a 95% CI using a random effect model. We calculated prevalence estimates and performed meta-regression to study the effect of age on live birth and miscarriage Main results and the role of chance We included 17 studies in our meta-analysis. One RCT compared two IUI cycles with two IVF cycles and found a halving of live birth (RR 0.46, 95% CI 0.25-0.86. n = 154), very low-quality evidence especially in view of the unfair comparison in treatment time. Pooling the data of five cohort studies that compared IU with IVF resulted in a comparable risk estimate, though the difference between IUI and IVF was not significantly different (RR 0.56, 95% CI 0.30-1.05, I2=73%, n = 7288), low quality evidence in view of the unequal distribution of female age over the groups and the heterogeneity. Meta-regression on data from IUI studies suggested that IUI above 43 years old resulted in pregnancy chances below 5% (3 studies n = 397, only women older than 40). Meta-regression on data from IVF studies (8 studies, n = 22 708) suggested that following IVF, live birth rates declined from about 20% at 38 years to 5% at 43 year and zero above 44 years. At the same time miscarriage rates increased from an estimate of 25% at 38 years old to more than 50% above a female age of 43 years. Limitations, reasons for caution Female age, a likely effect modifier, was not equally distributed in the cohort studies, especially in the small IUI cohort studies. The available evidence lacked information on duration of treatment. For a fair comparison the treatment time horizon should be equal. Wider implications of the findings It is expected that the average age of women trying to conceive will only further increase within the coming years. Findings of this systematic review underline the importance of a randomized controlled trial to provide more evidence on which treatment should be recommended for women &amp;gt; 38 with unexplained subfertility. Trial registration number Not applicable

P-033 Impact of the sperm reactive oxygen species on Intrauterine Insemination outcome

Abstract Study question Does sperm reactive oxygen species values affect the pregnancy rate after Intrauterine Insemination (IUI)? Summary answer Sperm reactive oxygen species values affect pregnancy rate and can be used as a predictive marker for IUI outcome. What is known already Oxidative stress resulting from excessive production of reactive oxygen species (ROS) can profoundly affect the sperm and subsequent functional sperm integrity. Diagnostics to measure semen oxidative stress have been added to the 6th edition of the WHO laboratory manual for examining and processing of human semen, under advanced examinations. Although a semen analysis has classically been used as the gold standard for determining a man’s fertility, basic sperm analysis alone cannot accurately predict infertility since between 6 and 27 % of men with normal semen parameters are infertile. Determination of oxidative stress in diagnosing infertility may contribute to better outcomes. Study design, size, duration This study was based on semen analyses of 50 male patients whose samples were used for IUI treatment between November 2022 and January 2023. The oxidation-reduction potential was measured using novel galvanostat-based technology, the MiOXSYS System. Briefly, 30 μL of liquefied semen at room temperature were applied to the MiOXSYS sensor. Both absolute ORP (mV) and normalized sORP values ( mV/10 6 sperm/ml) based on sperm concentration were calculated. Participants/materials, setting, methods Sperm analysis were performed according to the WHO laboratory manual sperm criteria (Sixth edition 2021). All participants followed a period of 3–5 days of sexual abstinence and had a diagnosis of unexplained infertility (normozoospermia). Ovarian stimulation for IUI cycle was initiated on the 5th day of menstruation by using recombinant gonadotropins. Clinical pregnancy was determined based on the Beta-hCG values. For statistical comparison between group values the Mann-Whitney U test was used. Main results and the role of chance According to the guidelines of the World Health Organization, all participants included in the study had normal BMI (21.85±3.80 kg/m2). The average age of the female patients included in the study was 33.9 ± 3.1 years while the average age of the male patients was 37.8 ± 4.8 years. Out of the 50 patients, 32% (N = 16) got pregnant. For the study propose sperm ORP and sORP values were compared between patients based on the pregnancy outcome. Statistical analysis showed a significant difference in ORP values. Patients with a positive pregnancy outcome after IUI had a lower ORP value compared to patients where IUI was not successful [25.65 [6.7-52.6] mV vs. 40.2 [6.3-109.8] mV, respectively, p = 0.02]. Additionally, normalized values according to the sperm concentration (sORP) were also significantly different between those groups [ 0.37(0.17-1.44) mV/10 6 sperm/ml vs. 0.88(0.13-20.81) mV/10 6 sperm/ml, respectively p = 0.006]. Due to the above-mentioned significant difference logistic regression analysis were performed, and the obtained results confirm that sperm ORP (p = 0.02) as well sORP (p = 0.016) significantly affects the pregnancy rate after the IUI procedure. Limitations, reasons for caution The limitation of the presented study was a relatively small patient cohort. Additionally, pregnancy was determined based on the beta hCG values, therefore future research should link ORP values and live birth rate as well. Wider implications of the findings In the present study suggests ORP as an additional parameter with diagnostic value to identify the best therapeutic approach concerning IUI in couples that show minimal or no impairments of the WHO semen parameter. Trial registration number not applicable

O-023 ‘The PiNC Trial’: Progesterone in Natural Cycles for the treatment of unexplained infertility

Abstract Study question Does exogenous progesterone for luteal phase support in natural cycles affect the biochemical, clinical pregnancy, livebirth or miscarriage rates in women with unexplained infertility (UI)? Summary answer Progesterone luteal support lead to an increase in livebirth rate from 7% to 15.3% and a decrease in miscarriage rates from 40% to 20%. What is known already Unexplained infertility is a diagnosis likely to encompass a population with varying underlying subtle pathologies. The only treatments currently recommended for treating UI are intrauterine insemination (IUI) and IVF/ICSI which are both expensive and invasive. The evidence for IUI with and without controlled ovarian hyperstimulation (COH) is inconclusive. A recent systematic review and meta-analysis reported a progesterone-mediated reduction in endometrial receptivity as a possible mechanism in the pathogenesis of UI. No trial has been published investigating the effectiveness of exogenous progesterone for luteal support in otherwise natural, unmedicated cycles to improve reproductive outcomes in couples with UI. Study design, size, duration We conducted an open-label, parallel arm, single centre, randomised controlled trial of an investigational medicinal product (cTIMP) from February 2020 to November 2022. We randomised 143 couples with UI to either luteal phase progesterone support or no luteal phase support and analysed the results on an intention-to-treat basis. Each couple participated for 3 menstrual cycles and they were followed up until either the end of a 3rd non-conceptual cycle or any resulting pregnancy. Participants/materials, setting, methods Couples with normal semen analysis (WHO 2020), regular ovulation, bilateral patent tubes, female partner aged ≤42yrs and BMI ≤30 were recruited and randomised following screening and informed consent. Participants timed their luteinising hormone (LH) surge using digital ovulation kits and had timed intercourse for 3 cycles. The treatment group took progesterone suppositories 400mg bd for 14 days after the LH surge. All pregnancies were scanned at 6-7/40 and ongoing pregnancies followed up to delivery. Main results and the role of chance 143 couples were recruited and randomised. Livebirth rates were 11/72 (15.3%) in the treatment group vs. 5/71 (7.0%) in the control group (Odds Ratio (OR) 2.38, 95%CI 0.78-7.24). Biochemical pregnancy rates (defined by a positive urinary pregnancy test) were 15/72 (20.8%) (treatment) vs 10/71 (14.1%) (control) (OR 1.61, 95%CI 0.67-3.86). Clinical pregnancy rates (defined by a gestation sac seen on ultrasound at a minimum of 6/40 gestation) were 14/72 (19.4%) (treatment) vs 9/71 (12.7%) (control) (OR 1.66, 95% CI 0.67-4.13). The miscarriage rate including biochemical losses was 3/15 (20%) of all pregnancies (treatment) vs. 4/10 (40%) (control). One pregnancy in the control group was terminated due to fetal anomalies. There was one ectopic pregnancy in the treatment group. Logistic regression demonstrated that none of the pregnancy outcomes were affected by participant age, BMI, ovarian reserve markers, previous parity or semen analysis parameters. The two participants in the treatment group who experienced miscarriages were both off-protocol. Although the results did not reach statistical significance, the 15.3% livebirth rate and OR of 2.37 for livebirths are clinically significant (equivalent to the success rates of stimulated intrauterine insemination treatment) as is the miscarriage rate of 0/11 clinical intra-uterine pregnancies for women taking progesterone as per protocol.Limitations, reasons for caution Despite the lack of statistical significance, differences in livebirth and miscarriage rates are clinically significant compared with alternative treatments. The trial was unblinded but the objective outcomes are unlikely to be affected by this. A larger trial using the effect size from this study to guide sample size is planned. Wider implications of the findings The treatment investigated here represents a simple, non-invasive and inexpensive option that is acceptable to couples with UI and may increase their chance of pregnancy and livebirth. If this treatment offers similar success rates to stimulated IUI it is likely to become a first-line option for many couple worldwide. Trial registration number 2019-003468-27

Impact of tubal patency test selection on the live birth rate following intrauterine insemination in couples with unexplained infertility: a retrospective cohort study.

We planned a study to evaluate the impact of selecting hysterosalpingography (HSG) over diagnostic laparoscopy during initial fertility evaluation on IUI treatment outcomes in couples diagnosed with unexplained infertility. The study comprised a retrospective cohort and included couples evaluated for infertility at our tertiary level hospital between January 2008 and December 2019. Couples diagnosed with unexplained infertility based on tubal patency tests (either HSG or diagnostic laparoscopy) were included. We compared outcomes following ovarian stimulation (OS) and intrauterine insemination (IUI) between women who underwent HSG versus laparoscopy for up to three treatment cycles. A total of 7413 women were screened, out of which 1002 women were diagnosed with unexplained infertility. We did not find a significant statistical difference in the clinical pregnancy (16.7% vs. 11.7%; OR (odds ratio) 1.51; 95% CI (confidence interval) 0.90-2.5) or live birth rate per IUI cycle (15.1% vs. 10.7%; OR 1.51, 95% CI 0.9-2.6) in women who underwent HSG for tubal evaluation as compared to laparoscopy. After adjustment for potential confounders through multivariate analysis, we found that outcomes were comparable between the HSG and laparoscopy. The current study did not find any significant difference in treatment outcomes following OS and IUI in women with unexplained infertility who underwent HSG compared to laparoscopy for the assessment of the tubal patency during the initial fertility workup. The finding suggests minimal or no impact of selecting HSG over diagnostic laparoscopy as a tubal patency test on the subsequent IUI outcomes.

Factors associated with spontaneous miscarriage risk in IUI treatment: A retrospectively cohort of 31,933 cycles

To determine the factors associated with intrauterine insemination (IUI) miscarriages and reduce the IUI miscarriage rate, a retrospective study was performed by reviewing 31,933 IUI cycles from 2006 to 2018. The overall there were 14.50% clinical pregnancies, and 16.74% miscarriages. Logistic regression revealed the following three predictive variables: females aged ≥ 35 years (odds ratio [OR] = 2.131; p < 0.001), spontaneous miscarriage history (OR = 1.513; p = 0.005), and ovarian stimulation schemes such as clomiphene citrate (CC) (OR = 1.459; p = 0.003). The natural cycle led to a lower miscarriage rate for patients without spontaneous miscarriage history both for those over 35 years old (OR = 0.402; p = 0.034) and for those under 35 years old (OR = 0.806; p = 0.017). Gonadotropin (Gn) showed the lowest miscarriage rate for patients without abortion history, though no significant differences were found. Patients under 35 with a history of miscarriage were protected from miscarriage by using CC and Gn together (OR = 0.516; p = 0.032). No significant differences were found between various ovarian protocols when patients with abortion history were aged ≥ 35 years (p = 0.606). CC + Gn showed the lowest miscarriage rate. In conclusion, the natural cycle could be suggested for infertility couples to minimize abortion risk. When ovarian induction is required, CC + Gn had the lowest miscarriage rate for women with a history of spontaneous miscarriage while Gn is more successful for individuals without such a history.

Hypersecretion of basal luteinizing hormone and an increased risk of pregnancy loss among women with polycystic ovary syndrome undergoing controlled ovarian stimulation and intrauterine insemination

IntroductionThe relationship between basal luteinizing hormone (LH) and reproductive outcomes in women with polycystic ovary syndrome (PCOS) undergoing intrauterine insemination (IUI) has remained largely unknown, warranting further investigations. Accordingly, this study aimed to investigate the possible association of basal LH with reproductive outcomes in women with PCOS women undergoing IUI to gain a better understanding of this topic. Material and methodsData from 533 cycles of controlled ovarian stimulation (COS) and IUI treatments from PCOS women were retrospectively analyzed. Statistical methods, including univariate analysis, receiver operating characteristic (ROC) curve, quartile division, and Spearman rank correlation analysis, were utilized. ResultsBasal LH resulted as the most significant contributor to pregnancy (P < 0.001). ROC analysis revealed that the predictive power of basal LH on pregnancy was stronger compared to other factors (areas under the curve 0.614, 95% CI 0.558–0.670, P = 0.000). Analysis based on quartile division unveiled a stair-shaped relation of basal LH with pregnancy or live birth as well as a positive linear relation between basal LH and early miscarriage (all P trend<0.05). Basal LH of 11.69 mIU/ml was the point above which early miscarriage grew significantly while pregnancies and live births ceased to increase. Moreover, basal LH was positively correlated with antral follicle count (AFC), number of mature follicles on the trigger day, clinical pregnancy, live birth, and multiple pregnancies (all P < 0.05). The number of mature follicles on the trigger day was positively correlated with clinical pregnancy, early miscarriage, and multiple pregnancies (all P < 0.05). AFC was positively correlated with clinical pregnancy (P < 0.05). ConclusionHypersecretion of basal LH was associated with an increased risk of pregnancy loss among PCOS women undergoing COS and IUI. Basal LH may have predictive value on pregnancy achievement in women with PCOS undergoing COS and IUI.