In vitro fertilisation for unexplained subfertility.

BACKGROUND: In vitro fertilisation (IVF) is a treatment for unexplained subfertility but is invasive, expensive, and associated with risks. OBJECTIVES: To evaluate the effectiveness and safety of IVF versus expectant management, unstimulated intrauterine insemination (IUI), and IUI with ovarian stimulation using gonadotropins, clomiphene citrate (CC), or letrozole in improving pregnancy outcomes. SEARCH METHODS: We searched following databases from inception to November 2021, with no language restriction: Cochrane Gynaecology and Fertility Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL. We searched reference lists of articles and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing effectiveness of IVF for unexplained subfertility with expectant management, unstimulated IUI, and stimulated IUI. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: IVF versus expectant management (two RCTs) We are uncertain whether IVF improves live birth rate (LBR) and clinical pregnancy rate (CPR) compared to expectant management (odds ratio (OR) 22.0, 95% confidence interval (CI) 2.56 to 189.37; 1 RCT; 51 women; very low-quality evidence; OR 3.24, 95% CI 1.07 to 9.8; 2 RCTs; 86 women; I2 = 80%; very low-quality evidence). Adverse effects were not reported. Assuming 4% LBR and 12% CPR with expectant management, these would be 8.8% to 9% and 13% to 58% with IVF. IVF versus unstimulated IUI (two RCTs) IVF may improve LBR compared to unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12; 2 RCTs; 156 women; I2 = 60%; low-quality evidence). We are uncertain whether there is a difference between IVF and IUI for multiple pregnancy rate (MPR) (OR 1.03, 95% CI 0.04 to 27.29; 1 RCT; 43 women; very low-quality evidence) and miscarriage rate (OR 1.72, 95% CI 0.14 to 21.25; 1 RCT; 43 women; very low-quality evidence). No study reported ovarian hyperstimulation syndrome (OHSS). Assuming 16% LBR, 3% MPR, and 6% miscarriage rate with unstimulated IUI, these outcomes would be 18.5% to 49%, 0.1% to 46%, and 0.9% to 58% with IVF. IVF versus IUI + ovarian stimulation with gonadotropins (6 RCTs), CC (1 RCT), or letrozole (no RCTs) Stratified analysis was based on pretreatment status. Treatment-naive women There may be little or no difference in LBR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.19, 95% CI 0.87 to 1.61; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 1.63, 95% CI 0.91 to 2.92; 2 RCTs; 221 women; I2 = 54%; low-quality evidence); or between IVF and IUI + CC (OR 2.51, 95% CI 0.96 to 6.55; 1 RCT; 103 women; low-quality evidence). Assuming 42% LBR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 26% LBR with IUI + gonadotropins (1 IVF to 1 IUI cycle), LBR would be 39% to 54% and 24% to 51% with IVF. Assuming 15% LBR with IUI + CC, LBR would be 15% to 54% with IVF. There may be little or no difference in CPR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.17, 95% CI 0.85 to 1.59; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 4.59, 95% CI 1.86 to 11.35; 1 RCT; 103 women; low-quality evidence); or between IVF and IUI + CC (OR 3.58, 95% CI 1.51 to 8.49; 1 RCT; 103 women; low-quality evidence). Assuming 48% CPR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 17% with IUI + gonadotropins (1 IVF to 1 IUI cycle), CPR would be 44% to 60% and 28% to 70% with IVF. Assuming 21% CPR with IUI + CC, CPR would be 29% to 69% with IVF. There may be little or no difference in multiple pregnancy rate (MPR) between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 0.82, 95% CI 0.38 to 1.77; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 0.76, 95% CI 0.36 to 1.58; 2 RCTs; 221 women; I2 = 0%; low-quality evidence); or between IVF and IUI + CC (OR 0.64, 95% CI 0.17 to 2.41; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in OHSS between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 6.86, 95% CI 0.35 to 134.59; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference in OHSS with 1 IVF to 1 IUI cycle (OR 1.22, 95% CI 0.36 to 4.16; 2 RCTs; 221 women; I2 = 0%; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.53, 95% CI 0.24 to 9.57; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in miscarriage rate between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 0.31, 95% CI 0.03 to 3.04; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference with 1 IVF to 1 IUI cycle (OR 1.16, 95% CI 0.44 to 3.02; 1 RCT; 103 women; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.48, 95% CI 0.54 to 4.05; 1 RCT; 102 women; low-quality evidence). In women pretreated with IUI + CC IVF may improve LBR compared with IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57; 1 RCT; 280 women; low-quality evidence). Assuming 22% LBR with IUI + gonadotropins, LBR would be 39% to 65% with IVF. IVF may improve CPR compared with IUI + gonadotropins (OR 14.13, 95% CI 7.57 to 26.38; 1 RCT; 280 women; low-quality evidence). Assuming 30% CPR with IUI + gonadotropins, CPR would be 76% to 92% with IVF. AUTHORS' CONCLUSIONS: IVF may improve LBR over unstimulated IUI. Data should be interpreted with caution as overall evidence quality was low.

No adverse effect of confirmation of ovulation by rectal palpation and ultrasonography after artificial insemination on formation, development, and function of the corpus luteum and conception rate in cows.

The effect of confirmation of ovulation by rectal palpation and ultrasonography after artificial insemination (AI) on the development of the corpus luteum (CL) and conception rate was investigated in cows. A total of 90 clinically healthy Holstein-Friesian dairy cows were examined in this study. After AI, the cows were divided into three groups (30 cows per group). In Group I, ovulation was confirmed by rectal palpation at 24 h after AI. In Group II, ovulation was confirmed using transrectal ultrasonography 24 h after AI. In Group III, ovulation was not confirmed after AI. Day 0 was defined as the day when ovulation was confirmed in Groups I and II, and as the day after AI was performed in group III. Transrectal ultrasonography was performed on days 3, 5, 7, and 14 to measure the CL diameter, tissue area, and CL blood flow area, and the ratio of CL blood flow area to CL tissue area was calculated. On the day of CL measurement, blood samples were collected to determine the plasma concentrations of progesterone (P4) and estradiol-17ß (E2). Pregnancy was diagnosed at 28 and 60 days after AI. A high conception rate of approximately 80% was achieved in Groups I and II, in which confirmation of ovulation was conducted. There were no differences in the diameter, tissue area, or blood flow area of the CL between the three groups. These results indicate that the confirmation of ovulation by rectal palpation and transrectal ultrasonography did not affect the formation and function of the CL or conception rate.

Impact of prolonged one or more natural menstrual cycles on the outcomes of ovulation induction intrauterine artificial insemination pregnancy: a single-centre, retrospective study in China.

OBJECTIVES: We determined if the time interval between two ovulation induction intrauterine artificial insemination (IUI) treatment cycles should be extended by one or more natural menstrual cycles in patients undergoing successive cycles of ovulation stimulation, and whether this affects clinical pregnancy rate (CPR). DESIGN: This study was conducted on infertility patients treated under the ovulation induction programme IUI in a large reproductive centre in China. Study participants were assigned into continuous and discontinuous groups. Differences in baseline clinical pregnancy and abortion rates were compared between the groups. A multivariate logistic model was used to evaluate the effects of time interval on clinical pregnancy outcomes. SETTING: Reproductive Centre of Maternal and Child Health Hospital of Lianyungang city. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was CPR, the secondary outcome measure was the abortion rate. RESULTS: A total of 550 IUI treatment cycles involving 275 couples were included in this study. Differences in CPR and abortion rate between the groups were not significant (20.5% vs 21.9% and 27.8% vs 22.0%, p≥0.05). Stratified analyses based on infertility factors did not reveal any significant differences in pregnancy and abortion rates between the groups (p≥0.05). Multivariate analysis showed that increased endometrial thickness correlates with CPR (OR 1.205, 95% CI 1.05 to 1.384, p=0.008). Compared with primary infertility, secondary infertility significantly correlated with improved CPR (OR 2.637, 95% CI 1.313 to 5.298, p=0.006). The effects of time interval between the first two ovulation induction IUI treatment cycles on clinical pregnancy were not significant (OR 1.007, 95% CI 0.513 to 1.974, p=0.985). CONCLUSIONS: Longer time intervals between the first two ovulation induction IUI treatment cycles did not significantly improve CPR. Therefore, in the absence of clear clinical indications, it may not be necessary to deliberately prolong the interval between two ovulation induction IUI treatment cycles.

Effectiveness and safety of intrauterine insemination vs. assisted reproductive technology: emulating a target trial using an observational database of administrative claims.

OBJECTIVE: To compare the effectiveness and safety of 1 cycle of assisted reproductive technology (ART) vs. 3 cycles of intrauterine insemination (IUI). DESIGN: Target trial emulation using observational data. SETTING: A healthcare claims database (2011-2015). PATIENT(S): The patients were 29,021 women aged 18-45 years with an infertility diagnosis and no history of IUI or ART within the past 12 months. INTERVENTION(S): One ART cycle immediately, with no more cycles of ART or IUI within the next 4 months; or 1 IUI cycle immediately, with 2 additional consecutive cycles of IUI within the next 4 months unless pregnancy occurred. MAIN OUTCOME MEASURE(S): Live births, multiple births, congenital malformations, preterm births, small-for-gestational-age newborns, large-for-gestational-age newborns, admission to neonatal intensive care unit (NICU), gestational diabetes, preeclampsia, and gestational hypertension. RESULT(S): The probability of live birth was 27.3% for ART and 26.3% for IUI. The observational analogue of per-protocol risk difference (95% confidence interval) for ART compared with IUI was 1.0% (-0.1%, 2.2%) for live births, 4.3% (3.7%, 4.9%) for multiple births, 3.4% (2.8%, 4.0%) for preterm births, 1.5% (0.9%, 2.1%) for NICU admissions, and 0.6% (0.2%, 1.0%) for gestational diabetes. The risk differences for the other outcomes were <0.5%. The results of the 2 strategies were similar in women ≤40 years, but in women >40 years the probability of live birth was greater for ART (14.4%) than for IUI (7.4%). CONCLUSION(S): Compared with 3 cycles of IUI, 1 cycle of ART was estimated to have a similar probability of live birth but slightly higher risks of multiple gestations, preterm births, and NICU admissions.

The Risk of Highly Pathogenic Influenza A Virus Transmission to Turkey Hen Flocks Through Artificial Insemination.

Artificial insemination is a routine practice for turkeys that can introduce pathogens into breeder flocks in a variety of ways. In this manuscript, a risk analysis on the potential transmission of highly pathogenic avian influenza (HPAI) to naïve hens through artificial insemination is presented. A case of HPAI on a stud farm where the potential transmission of the virus to susceptible hens in the 2015 H5N2 HPAI outbreak in Minnesota is described along with documentation of known and potential transmission pathways from the case. The pathways by which artificial insemination might result in the spread of HPAI to susceptible hens were determined by considering which could result in the 1) entry of HPAI virus onto a premises through semen movement; and 2) exposure of susceptible hens to HPAI as a result of this movement. In the reported case, HPAI virus was detected in semen from infected toms, however, transmission of HPAI to naïve hens through semen is unclear since the in utero infectious dose is not known. This means that the early detection of infection might limit but not eliminate the risk of hen exposure. Because of the numerous potential pathways of spread and the close contact with the birds, it is highly likely that if semen from an HPAI-infected tom flock is used, there will be spread of the virus to naïve hens through insemination. If insemination occurs with semen from stud farms in an HPAI control area, receiving hen farms should have restricted movements to prevent outbreak spread in the event that they become infected.

Artículo regular­Riesgo de transmisión del virus de la influenza A altamente patógeno a parvadas de pavos hembras mediante inseminación artificial. La inseminación artificial es una práctica de rutina para los pavos que puede introducir patógenos en las parvadas de reproductores de diversas formas. En este manuscrito, se presenta un análisis de riesgo sobre la posible transmisión de la influenza aviar altamente patógena a gallinas susceptibles mediante inseminación artificial. Un caso de influenza aviar altamente patógena en una granja de machos sementales donde se describe la posible transmisión del virus a gallinas susceptibles en el brote de influenza aviar altamente patógena H5N2 del año 2015 en Minnesota, junto con la documentación de las vías de transmisión conocidas y potenciales del caso. Las vías por las cuales la inseminación artificial podría resultar en la propagación de la influenza aviar altamente patógena a las gallinas susceptibles se determinaron considerando cuáles podrían resultar en 1) la entrada del virus de la influenza aviar altamente patógena en una granja a través del movimiento del semen; y 2) exposición de gallinas susceptibles a la influenza aviar altamente patógena como resultado de este movimiento. Sin embargo, se demostró la detección del virus de la influenza aviar altamente patógena en el semen de machos infectados. Debido a que se desconoce la dosis infecciosa del virus de la influenza aviar administrada en el útero necesaria para transmitir la influenza aviar altamente patógena a las gallinas susceptibles, está claro que la detección de la infección no puede ser la única estrategia de contención. La detección temprana de la infección puede limitar, pero no eliminar, el riesgo de exposición de las gallinas. Debido a las numerosas vías potenciales de propagación y al estrecho contacto con las aves, es muy probable que si se usa semen de una parvada de machos infectados con influenza aviar de alta patogenicidad, se propague el virus a gallinas susceptibles a través de la inseminación. Si la inseminación ocurre con semen de granjas de sementales en un área de control de influenza aviar de alta patogenicidad, las granjas de gallinas receptoras deben tener movimientos restringidos para prevenir la propagación del brote en caso de que se infecten.

Transmission of Bluetongue Virus Serotype 8 by Artificial Insemination with Frozen-Thawed Semen from Naturally Infected Bulls.

Transmission of bluetongue (BT) virus serotype 8 (BTV-8) via artificial insemination of contaminated frozen semen from naturally infected bulls was investigated in two independent experiments. Healthy, BT negative heifers were hormonally synchronized and artificially inseminated at oestrus. In total, six groups of three heifers received semen from four batches derived from three bulls naturally infected with BTV-8. Each experiment included one control heifer that was not inseminated and that remained BT negative throughout. BTV viraemia and seroconversion were determined in 8 out of 18 inseminated heifers, and BTV was isolated from five of these animals. These eight heifers only displayed mild clinical signs of BT, if any at all, but six of them experienced pregnancy loss between weeks four and eight of gestation, and five of them became BT PCR and antibody positive. The other two infected heifers gave birth at term to two healthy and BT negative calves. The BT viral load varied among the semen batches used and this had a significant impact on the infection rate, the time of onset of viraemia post artificial insemination, and the gestational stage at which pregnancy loss occurred. These results, which confirm unusual features of BTV-8 infection, should not be extrapolated to infection with other BTV strains without thorough evaluation. This study also adds weight to the hypothesis that the re-emergence of BTV-8 in France in 2015 may be attributable to the use of contaminated bovine semen.

The association of adverse outcomes with pregnancy conception methods among low-risk term pregnancies.

OBJECTIVE: To compare composite neonatal and maternal adverse outcomes among low-risk singleton pregnancies at 37-41 weeks among conception methods: spontaneously-conceived (SC) pregnancy; infertility medications and/or intrauterine insemination (IFM/IUI); and assisted reproductive technology (ART). DESIGN: Population-based retrospective cohort study. SETTING: US Vital Statistics datasets 2013-2017. PATIENT(S): Low-risk pregnancies (without hypertensive disorders, pregestational or gestational diabetes, or history of preterm birth) of women ≥20 years with nonanomalous singletons, who labored, delivered at 37-41 weeks, and had data on pregnancy conception method. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was the composite neonatal adverse outcome (CNAO). The secondary outcome was the composite maternal adverse outcome (CMAO). RESULT(S): Of the 19.7 million deliveries during the study period, 54.0% (N = 10,676,184) met the inclusion criteria, with 99.0% (N = 10,573,741) being conceived spontaneously, 0.4% (N = 47,227) by IFM/IUI, and 0.5% (N = 55,216) by ART. The overall rate of CNAO was 6.68 per 1,000 live births. Compared with SC, the risk of CNAO was significantly higher among IFM/IUI (adjusted relative risk [aRR], 1.29; 95% CI, 1.18-1.41) and ART (aRR, 1.29; 95% CI, 1.18-1.39). The overall rate of CMAO was 2.50 per 1,000 live births. Compared with SC, the risk of CMAO was significantly increased among IFM/IUI (aRR, 1.72; 95% CI, 1.50-1.97) and ART (aRR, 2.40; 95% CI, 2.17-2.65). CONCLUSION(S): Among low-risk term singleton pregnancies, IFM/IUI and ART have modestly higher rates of adverse outcomes to maternal-neonatal dyad than SC.

Clarifying the relationship between total motile sperm counts and intrauterine insemination pregnancy rates.

OBJECTIVE: To study the relationship between postwash total motile sperm count (TMSC) and intrauterine insemination (IUI) outcomes. DESIGN: Retrospective review SETTING: Large fertility clinic PATIENT(S): A total of 92,471 insemination cycles from 37,553 patients were included in this study. INTERVENTION(S): All stimulated clomiphene citrate, letrozole, and/or injectable gonadotropin IUI cycles performed at a single institution from 2002 through 2018 were reviewed. Generalized estimating equations (GEE) analysis was used to account for multiple cycles by individual patients and to adjust for female partner age, body mass index, and stimulation protocol. MAIN OUTCOME MEASURE(S): Successful clinical pregnancy was defined as ultrasound confirmation of an intrauterine gestational sac with fetal cardiac activity. RESULT(S): A total of 92,471 insemination cycles were available to evaluate the relationship between postwash TMSC and clinical pregnancy. Pregnancy rates were highest with TMSC of ≥9 × 106 and declined gradually as TMSC decreased. Complete data for the adjusted GEE analysis were available for 62,758 cycles. Adjusted GEE analysis among cycles with TMSC of ≥9 × 106 (n = 46,557) confirmed that TMSC in this range was unrelated to pregnancy. Conversely, TMSC was highly predictive of pregnancy (Wald χ2 = 39.85) in adjusted GEE analysis among cycles with TMSC of <9 × 106 (n = 16,201), with a statistically significant decline. CONCLUSIONS: IUI pregnancy is optimized with TMSC of ≥9 × 106, below which the rates gradually decline. Although rare, pregnancies were achieved with TMSC of <0.25 × 106. Since the decline in pregnancy is gradual and continuous, there is no specific threshold above which IUI should be recommended. Rather, these more specific quantitative predictions can be used to provide personalized counseling and guide clinical decision making.

A unique case of diagnosis of a heterotopic pregnancy at 26 weeks - case report and literature review.

BACKGROUND: Heterotopic pregnancy (HP) is a rare condition when at least two pregnancies are present simultaneously at different implantation sites and only one located in the uterine cavity. The majority of cases are diagnosed in the first trimester. CASE PRESENTATION: We present a unique case of HP diagnosed at 26 weeks of spontaneous pregnancy in a patient without any relevant risk factors. We performed an extensive review of HP cases from MEDLINE (PUBMED) published in English between 2005-2019 to prove this case's uniqueness. A 24-year-old woman presented because of threatened preterm birth. Despite treatment, pain aggravated, without progression of labor. An emergency ultrasound exam revealed free fluid in the abdominal cavity. Suspicion of active bleeding prompted the medical team to perform an exploratory laparotomy. The surgery team found a ruptured heterotopic pregnancy. This was an unexpected cause of nontraumatic hemoperitoneum at such advanced gestational age. The postoperative period was uneventful, and the intrauterine pregnancy continued to term. The final review included 86 out of 124 records. A total number of 509 cases were identified, but not all of them had complete data. The maximum reported gestational age at the time of diagnosis was 16 weeks of pregnancy, while our case became symptomatic and was diagnosed at 26 weeks of pregnancy. CONCLUSIONS: Regardless of pregnancy age, HP can be a cause of hemoperitoneum, and it should be included in the differential diagnosis of acute abdomen in the second trimester.

Treatment Strategies for Unexplained Infertility.

Unexplained infertility is a common diagnosis among couples with infertility. Pragmatic treatment options in these couples are directed at trying to improve chances to conceive, and consequently intrauterine insemination (IUI) with ovarian stimulation and in vitro fertilization (IVF) are standard clinical practice, while expectant management remains an important alternative. While evidence on IVF or IUI with ovarian stimulation versus expectant management was inconclusive, these interventions seem more effective in couples with a poor prognosis of natural conception. Strategies such as strict cancellation criteria and single-embryo transfer aim to reduce multiple pregnancies without compromising cumulative live birth. We propose a prognosis-based approach to manage couples with unexplained infertility so as to expose less couples to unnecessary interventions and less mothers and children to the potential adverse effects of ovarian stimulation or laboratory procedures.

Oxidative stress biomarkers in newborn calves: Comparison among artificial insemination, in vitro fertilization and cloning.

Oxidative stress occurs when there is greater than optimal production of reactive oxygen species (ROS) or an antioxidant system failure. Calves produced using in vitro fertilization (IVF) or cloning (CA) have greater mortality rates, with greater incidence of respiratory diseases, which could be explained by the deleterious outcomes from oxidative stress. Calves were studied that were produced using: artificial insemination (AI; n = 20), in vitro fertilization (IVF; n = 15) or cloning (CA; n = 15). Blood samples were collected at 6, 12, 24 and 48 h subsequent to the time of birth. The cloned calves had greater ROS production from lipid peroxidation, with greater thiobarbituric acid reactive substances. This factor was associated with a lesser amount of superoxide dismutase in the CA. Calves produced using IVF had a greater activity of catalase and glutathione peroxidase, either due to greater production of hydrogen peroxide or greater efficiency of enzymatic response of these neonates. Calves produced using AI had greater concentrations ​​of reduced thiol groups. These associated factors may indicate there is greater oxidative stress in calves produced by IVF and cloning than with use of AI, however in these calves there was an effective response to these oxidative stressors within 48 h subsequent to birth. Hence, calves produced using IVF and by cloning have greater ROS production when compared to calves produced using AI. The calves produced using IVF, however, had a greater enzymatic activity or were more efficient in adapting to ROS when compared to calves produced by cloning.

Intra-uterine insemination for unexplained subfertility.

BACKGROUND: Intra-uterine insemination (IUI) is a widely-used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive than in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rates. OBJECTIVES: To determine whether, for couples with unexplained subfertility, the live birth rate is improved following IUI treatment with or without OH compared to timed intercourse (TI) or expectant management with or without OH, or following IUI treatment with OH compared to IUI in a natural cycle. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 17 October 2019, together with reference checking and contact with study authors for missing or unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing IUI with TI or expectant management, both in stimulated or natural cycles, or IUI in stimulated cycles with IUI in natural cycles in couples with unexplained subfertility. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, quality assessment and data extraction. Primary review outcomes were live birth rate and multiple pregnancy rate. MAIN RESULTS: We include 15 trials with 2068 women. The evidence was of very low to moderate quality. The main limitation was very serious imprecision. IUI in a natural cycle versus timed intercourse or expectant management in a natural cycle It is uncertain whether treatment with IUI in a natural cycle improves live birth rate compared to treatment with expectant management in a natural cycle (odds ratio (OR) 1.60, 95% confidence interval (CI) 0.92 to 2.78; 1 RCT, 334 women; low-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle to be 16%, that of IUI in a natural cycle would be between 15% and 34%. It is uncertain whether treatment with IUI in a natural cycle reduces multiple pregnancy rates compared to control (OR 0.50, 95% CI 0.04 to 5.53; 1 RCT, 334 women; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a stimulated cycle It is uncertain whether treatment with IUI in a stimulated cycle improves live birth rates compared to treatment with TI in a stimulated cycle (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs, 208 women; I2 = 72%; low-quality evidence). If we assume the chance of achieving a live birth with TI in a stimulated cycle was 26%, the chance with IUI in a stimulated cycle would be between 23% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle reduces multiple pregnancy rates compared to control (OR 1.46, 95% CI 0.55 to 3.87; 4 RCTs, 316 women; I2 = 0%; low-quality evidence). IUI in a stimulated cycle versus timed intercourse or expectant management in a natural cycle In couples with a low prediction score of natural conception, treatment with IUI combined with clomiphene citrate or letrozole probably results in a higher live birth rate compared to treatment with expectant management in a natural cycle (OR 4.48, 95% CI 2.00 to 10.01; 1 RCT; 201 women; moderate-quality evidence). If we assume the chance of a live birth with expectant management in a natural cycle was 9%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 50%. It is uncertain whether treatment with IUI in a stimulated cycle results in a lower multiple pregnancy rate compared to control (OR 3.01, 95% CI 0.47 to 19.28; 2 RCTs, 454 women; I2 = 0%; low-quality evidence). IUI in a natural cycle versus timed intercourse or expectant management in a stimulated cycle Treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with expectant management in a stimulated cycle (OR 1.95, 95% CI 1.10 to 3.44; 1 RCT, 342 women: moderate-quality evidence). If we assume the chance of a live birth with expectant management in a stimulated cycle was 13%, the chance of a live birth with IUI in a natural cycle would be between 14% and 34%. It is uncertain whether treatment with IUI in a natural cycle results in a lower multiple pregnancy rate compared to control (OR 1.05, 95% CI 0.07 to 16.90; 1 RCT, 342 women; low-quality evidence). IUI in a stimulated cycle versus IUI in a natural cycle Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle (OR 2.07, 95% CI 1.22 to 3.50; 4 RCTs, 396 women; I2 = 0%; low-quality evidence). If we assume the chance of a live birth with IUI in a natural cycle was 14%, the chance of a live birth with IUI in a stimulated cycle would be between 17% and 36%. It is uncertain whether treatment with IUI in a stimulated cycle results in a higher multiple pregnancy rate compared to control (OR 3.00, 95% CI 0.11 to 78.27; 2 RCTs, 65 women; low-quality evidence). AUTHORS' CONCLUSIONS: Due to insufficient data, it is uncertain whether treatment with IUI with or without OH compared to timed intercourse or expectant management with or without OH improves cumulative live birth rates with acceptable multiple pregnancy rates in couples with unexplained subfertility. However, treatment with IUI with OH probably results in a higher cumulative live birth rate compared to expectant management without OH in couples with a low prediction score of natural conception. Similarly, treatment with IUI in a natural cycle probably results in a higher cumulative live birth rate compared to treatment with timed intercourse with OH. Treatment with IUI in a stimulated cycle may result in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle.

Observational retrospective study of UK national success, risks and costs for 319,105 IVF/ICSI and 30,669 IUI treatment cycles.

OBJECTIVE: To compare success rates, associated risks and cost-effectiveness between intrauterine insemination (IUI) and in vitro fertilisation (IVF). DESIGN: Retrospective observational study. SETTING: The UK from 2012 to 2016. PARTICIPANTS: Data from Human Fertilisation and Embryology Authority's freedom of information request for 2012-2016 for IVF/ICSI (intracytoplasmic sperm injection)and IUI as practiced in 319 105 IVF/ICSI and 30 669 IUI cycles. Direct-cost calculations for maternal and neonatal expenditure per live birth (LB) was constructed using the cost of multiple birth model, with inflation-adjusted Bank of England index-linked data. A second direct-cost analysis evaluating the incremental cost-effective ratio (ICER) was modelled using the 2016 national mean (baseline) IVF and IUI success rates. OUTCOME MEASURES: LB, risks from IVF and IUI, and costs to gain 1 LB. RESULTS: This largest comprehensive analysis integrating success, risks and costs at a national level shows IUI is safer and more cost-effective than IVF treatment.IVF LB/cycle success was significantly better than IUI at 26.96% versus 11.49% (p<0.001) but the IUI success is much closer to IVF at 2.35:1, than previously considered. IVF remains a significant source of multiple gestation pregnancy (MGP) compared with IUI (RR (Relative Risk): 1.45 (1.31 to 1.60), p<0.001) as was the rate of twins (RR: 1.58, p<0.001).In 2016, IVF maternal and neonatal cost was £115 082 017 compared with £2 940 196 for IUI and this MGP-related perinatal cost is absorbed by the National Health Services. At baseline tariffs and success rates IUI was £42 558 cheaper than IVF to deliver 1LB with enhanced benefits with small improvements in IUI. Reliable levels of IVF-related MGP, OHSS (ovarian hyperstimulation syndrome), fetal reductions and terminations are revealed. CONCLUSION: IUI success rates are much closer to IVF than previously reported, more cost-effective in delivering 1 LB, and associated with lower risk of complications for maternal and neonatal complications. It is prudent to offer IUI before IVF nationally.

Seventy years of progestagen treatments for management of the sheep oestrous cycle: where we are and where we should go.

Management of the ovine oestrous cycle is mainly based on the use of exogenous hormones to mimic or enhance (progesterone and its analogues) or manipulate (prostaglandin F2α and its analogues) the activity of the corpus luteum, combined with the application of other hormones mimicking the pituitary secretion of gonadotrophins (e.g. equine chorionic gonadotrophin). These protocols have been applied without major change for decades but, now, there are two reasons to reconsider them: (1) our greatly improved knowledge of the dynamics of ovarian physiology, following the application of transrectal ultrasonography, indicates that modification of the protocols may improve fertility yields and (2) increasing concerns about animal health and welfare, food safety and the environmental impact of the treatments, as evidenced by public opinion and therefore market forces. Here, we offer an overview of these issues, introduce an updated protocol and suggest ways for future improvements to the protocols.

Understanding the correlation between artificial insemination and offspring health outcomes.

Although numerous articles have shown intracytoplasmic sperm injection and in vitro fertilization to be correlated with increased risk of disease, a few works have been published on the risks associated with artificial insemination. Meanwhile, questions about the possible causes underlying these correlations have remained in the background. The main objective of this work is not to review the risks associated with artificial insemination, but rather to describe how developmental processes may be affected by these techniques. Thus, we offer a theoretical framework for understanding the possible causes that underlie the correlation between low-complexity or milder techniques and offspring health outcomes.

A rare case of heterotopic quintuplets pregnancy.

OBJECTIVE: We report a rare case of heterotopic pregnancy and high-order pregnancy occurring simultaneously following the use of the assisted reproductive technique (ART). CASE REPORT: A 29-year-old woman, Gravida 2 Para 1, became pregnant after receiving intrauterine insemination (IUI). She came to our emergency room due to diffuse low abdominal pain at seven weeks of gestational age. Transabdominal sonography (TAS) revealed a quadruplet intrauterine pregnancy with an enlarged left adnexa and intrapelvic fluid accumulation. Simultaneous occurrence of high-order pregnancy and left tubal pregnancy with internal hemorrhage was suspected. The patient received an emergent laparoscopic resection of the affected Fallopian tube and recovered well for the remaining hospitalization course. Afterwards, she received fetal reduction procedure and eventually gave birth to twin babies. CONCLUSION: Gynecologist should increase the awareness of heterotopic pregnancy in patients receiving ART. On the other hand, reproductive endocrinologist should reduce the risk of high-order pregnancy without compromising pregnancy rate.

Fertility outcomes in patients with tubo-ovarian abscesses after an oocyte retrieval: a longitudinal cohort analysis.

PURPOSE: To determine the impact of pelvic inflammation caused by tubo-ovarian abscess (TOA) on ovarian response to stimulation. METHODS: This retrospective longitudinal cohort analysis that was carried out in a tertiary university-affiliated medical center included 15 women with TOA during in vitro fertilization (IVF) cycles. The ovarian response to stimulation and the pregnancy rate were compared in two subsequent cycles, the initial IVF cycle that was complicated by TOA after oocyte retrieval (first treatment cycle) and the following IVF treatment (second treatment cycle) that occurred within a period of a year from the first cycle. RESULTS: The mean number of retrieved oocytes was significantly higher in the first IVF cycle compared to the second cycle (8.1 ± 3.2 vs. 5.4 ± 2.5, P = .003], corresponding to a 30% reduction in ovarian response to gonadotropin stimulation. Fertilization rates were significantly lower in the second cycle (4.1 ± 2.9 vs. 2.9 ± 1.7, P = .015). Twelve women (80%) reached embryo transfer in the first cycle compared to 14 women (93.3%) in the second cycle. The mean number of transferred embryos was similar between the two cycles. There were no clinical pregnancies following the first cycle, and only one patient (6.6%) had a clinical pregnancy in the second treatment cycle. CONCLUSIONS: TOA following fertility treatment has a detrimental effect on ovarian function. The pregnancy rate in the immediate period following TOA is poor. Current data for recommending the deferral of fertility treatment following a TOA episode are insufficient, calling for more studies to address these issues.

Periovulatory administration of firocoxib did not alter ovulation rates and mitigated post-breeding inflammatory response in mares.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a therapeutic option for the treatment of inflammation. However, negative effects of non-selective NSAIDs for treatment of mares with endometritis have been described, including delayed uterine clearance and impairment of ovulations. Firocoxib is a specific cyclooxygenase-2 (COX-2) inhibitor and has the ability to act in the uterus of mares. We investigated the effects of firocoxib on ovulation rate, numbers of polymorphonuclear neutrophils (PMNs), and COX-2 protein levels in the endometrial tissue of susceptible mares after insemination. Two experiments were conducted. In experiment 1, twenty mares were evaluated in two consecutive estrous cycles broken into the following groups: Control - no pharmacological interference; Treatment - mares were treated with 0.2 mg/kg of firocoxib orally. The treatment began on the day of ovulation induction, and firocoxib was administered until one day after artificial insemination (AI). Ovulation was induced with 1 mg of deslorelin acetate and the mares were inseminated 24 h after the injection. Ovulation was confirmed 48 h after induction, and embryos were collected eight days after ovulation. Experiment 2: Nine mares susceptible to persistent mating-induced endometritis (PMIE) were artificially inseminated. The mares were examined with ultrasound and inseminated with fresh semen in two consecutive cycles, control and treated, in a cross-over study design. The amount of intrauterine fluid was measured, and endometrial samples were collected 24 h after AI. The number of PMNs was determined by endometrial cytology and biopsy, and COX-2 labeling in endometrial samples was evaluated by immunohistochemistry. Firocoxib treatment did not induce ovulatory failure or affect embryo recovery rate in Experiment 1. In Experiment 2, firocoxib treatment reduced inflammation after AI in mares as evidenced with results regarding PMN numbers/percentage and endometrial COX-2 staining. In conclusion, the proposed treatment with firocoxib reduced endometrial inflammation in mares susceptible to PMIE after breeding, with no adverse effects.

Presence of gammaherpesvirus BoHV-4 in endometrial cytology samples is not associated with subclinical endometritis diagnosed at artificial insemination in dairy cows.

In the past, bovine herpesvirus 4 (BoHV-4) has been suggested to be associated with metritis and endometritis. However, not many field studies investigated the association between BoHV-4 and subclinical endometritis (SCE). In the present study, the association between the intrauterine presence of BoHV-4 and SCE diagnosed during artificial insemination (AI) was examined on two dairy farms in Belgium. An immunoperoxidase monolayer assay (IPMA) and an enzyme-linked immuno sorbent assay (ELISA) were used to screen the serum for anti-BoHV-4 antibodies. A SYBR green based one step real time qPCR was used to detect and quantify BoHV-4 (ORF20) in nasal, uterine and vaginal samples collected at AI. A reverse transcription qPCR (RT-qPCR) was used to detect mRNA (gB) as proof of a productive BoHV-4 infection. BoHV-4 was detected in 39.4% (farm A)/23.8% (farm B) of the nasal samples, 48.5% (farm A)/19.0% (farm B) of the uterine samples and 51.5% (farm A)/42.9% (farm B) of the vaginal samples. Active replication was only detected in farm A in 38.5% of the BoHV-4 positive nasal samples and in 5.9% positive cases of the vaginal samples. The prevalence of SCE diagnosed at AI was 45.5% and 42.9% in farm A and farm B, respectively. The presence of SCE was associated with a reduced pregnancy outcome at artificial insemination (AI) (P＜0.001). The occurrence of SCE at AI was not associated with the presence of latent or productive BoHV4 infections in the uterus nor in the vagina and nose (P＞0.05).

Growing body of evidence supports intrauterine insemination as first line treatment and rejects unfounded concerns about its efficacy, risks and cost effectiveness.

IUI has been practiced for five decades but only three unconvincing trials attempted to demonstrate the superiority of IUI over sexual intercourse (SI). In the absence of evidence of its effectiveness, the National Institute for Clinical Excellence (NICE) recommended IVF over IUI after 2 years of unprotected SI. High-quality recent data in well-constructed studies suggest that biases against IUI procedures and in favour of IVF are invalid. It is unethical to continue to misinform patients and stakeholders. The well-constructed randomised controlled trials (RCT) show IUI procedure to be efficient, with minimal risk, and above all improved cost-effectiveness when compared to IVF for live birth. IUI as first-line treatment should be offered to most patients, while funding agencies and stakeholders need to be urgently informed of the cost-benefit in offering IUI. Fertility clinics, IVF interest groups, and regulatory bodies should amend their patient information and guidance to state that IUI should be the first line treatment and that IVF should be offered only when essential. Reappraising and promoting IUI based on evidence enhances patient autonomy, choices, and trust, while allowing the fertility industry to operate within an ethical and acceptable framework not seen as exploitative toward vulnerable patients.