Interventions for unexplained infertility: a systematic review and network meta-analysis

Effectiveness and Safety of IVF Add-Ons: A Meta-Review of 10 Common IVF Add-Ons

Lensen SF et al., 2025 · SSRN

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis

Melo P et al., 2023 · BJOG · Free to read

Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. Search Strategy: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. Selection Criteria: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. Data Collection and Analysis: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. MAIN The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I(2) = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I(2) = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I(2) = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I(2) = 0%; low-certainty evidence). Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.

Evidence-based guideline: unexplained infertility

Romualdi D et al., 2023 · Hum Reprod · Free full text on PubMed Central

Guideline Group on Unexplained Infertility; Romualdi D(1), Ata B(2)(3), Bhattacharya S(4), Bosch E(5), Costello M(6)(7), Gersak K(8), Homburg R(9), Mincheva M(10), Norman RJ(7)(11), Piltonen T(12), Dos Santos-Ribeiro S(13), Scicluna D(14), Somers S(15), Sunkara SK(16), Verhoeve HR(17), Le Clef N(18).

Ovarian Stimulation Strategies for Intrauterine Insemination in Couples with Unexplained Infertility - A Systematic Review and Individual Participant Data Meta-analysis

Wessel JA et al., 2022 · Fertility & Reproduction · Free to read

Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for couples with unexplained infertility. Individual participant data meta-analysis (IPD-MA) is the gold standard for evidence synthesis. To compare the effectiveness and safety of ovarian stimulation with gonadotrophin, Letrozole and clomiphene citrate (CC) and to explore treatment-covariate interactions for important baseline characteristics in women undergoing IUI. We searched electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). We included randomised controlled trials (RCTs) comparing IUI-OS with gonadotropins, Letrozole or CC among couples with unexplained infertility. We excluded dose comparing studies of the same drug. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. We used a one-stage approach using a random effects model. Six RCTs (n= 2299) provided IPD. Gonadotropins increased the chance of a live birth compared to both CC (5 RCTs, 1946 women, RR 1.28, 95%CI 1.10 to 1.49, I2 = 25%, moderate-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.77 95%CI 0.58 to 1.03). Gonadotropins increased the risk of a multiple pregnancy compared to both CC (4 RCTs, 1696 women, RR 2.17, 95%CI 1.33 to 3.55, I2 = 69%, low-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.71, 95%CI 0.33 to 1.56). No strong evidence on the treatment-covariate interactions (female age, BMI or primary versus secondary infertility) was found. Gonadotropins increased the chance of a live birth compared to both CC and Letrozole but also increased the chance of a multiple pregnancy. Further RCTs comparing Letrozole and other interventions in couples with unexplained infertility are needed.

In vitro fertilisation for unexplained subfertility

Pandian Z et al., 2012 · Cochrane Database Syst Rev

In vitro fertilisation (IVF) is a widely accepted treatment for unexplained infertility (NICE 2004), which affects up to a third of all infertile couples. With estimated live birth rates (LBRs) per cycle varying from 33.1% in women aged under 35 years down to 12.5% in women aged between 40 and 42 years (HFEA 2011), its effectiveness has not been rigorously evaluated in comparison with other treatments. With increasing awareness of the role of expectant management, less-invasive procedures such as intrauterine insemination (IUI), and concerns about multiple pregnancies and costs associated with IVF, it is important to evaluate the effectiveness of IVF against other treatment options in couples with unexplained infertility. To evaluate the effectiveness and safety of IVF compared to expectant management, clomiphene citrate, IUI alone and intrauterine insemination plus controlled ovarian stimulation (IUI+SO). Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, first quarter), MEDLINE (1970 to July 2011), EMBASE (1985 to July 2011) and reference lists of articles were searched. Relevant conference proceedings were handsearched. Authors were contacted. Selection Criteria: Randomised controlled trials (RCTs) were included. LBR per woman was the primary outcome. Data Collection and Analysis: Two review authors independently assessed eligibility and quality of trials. MAIN Six RCTs were included in the final analysis. LBR per woman was significantly higher with IVF (45.8%) than expectant management (3.7%) (odds ratio (OR) 22.00, 95% confidence interval (CI) 2.56 to 189.37, 1 RCT, 51 women). There were no comparative data for clomiphene citrate. There was no evidence of a significant difference in LBR between IVF and IUI alone (OR 1.96, 95% CI 0.88 to 4.36, 1 RCT, 113 women), 40.7% with IVF versus 25.9% with IUI. In studies comparing IVF versus IUI+SO, LBR per woman did not differ significantly between the groups among treatment-naive women (OR 1.09, 95% CI 0.74 to 1.59, 2 RCTs, 234 women) but was significantly higher in a large RCT of women pretreated with IUI + clomiphene citrate (OR 2.66, 95% CI 1.94 to 3.63, 1 RCT, 341 women). These three studies could not be pooled due to high heterogeneity (I(2) = 84%). There was no evidence of a significant difference in multiple pregnancy rate (MPR) or ovarian hyperstimulation syndrome (OHSS) between the two treatments (OR 0.64, 95% CI 0.31 to 1.29, 3 RCTs, 351 women; OR 1.53, 95% CI 0.25 to 9.49, 1 RCT, 118 women, respectively). AUTHORS' IVF may be more effective than IUI+SO. Due to paucity of data from RCTs the effectiveness of IVF for unexplained infertility relative to expectant management, clomiphene citrate and IUI alone remains unproven. Adverse events and the costs associated with these interventions have not been adequately assessed.

The definition of unexplained infertility: A systematic review

Raperport C et al., 2024 · BJOG : an international journal of obstetrics and gynaecology · Free to read

There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta-analysis and best practice advice. This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis. CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language. Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range. Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid-luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies. This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.

Diagnosis and treatment of unexplained infertility

Quaas A et al., 2008 · Rev Obstet Gynecol · Free full text on PubMed Central

Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.

The pregnancy outcomes of infertile women with polycystic ovary syndrome undergoing intrauterine insemination with different attempts of previous ovulation induction

Gao Y et al., 2022 · Frontiers in Endocrinology · Free full text on PubMed Central

Polycystic ovary syndrome (PCOS) is one of the most common reasons for infertility. The consensus of the treatment of infertile women with PCOS is ovulation induction (OI) for six to nine attempts beforein vitrofertilization (IVF)/intracytoplasmic sperm injection (ICSI). Nowadays, more attention was paid to a rising, noninvasive treatment, intrauterine insemination (IUI), as some experts claimed IUI could benefit PCOS patients with infertility. Our study means to investigate the outcomes of IUI for PCOS patients and if patients’ previous OI cycles can be a predictive factor for IUI outcomes. A total of 1,086 PCOS patients was included and 1,868 IUI cycles were performed between January 2007 and July 2021 in the department of assisted reproduction in Shanghai Ninth People’s Hospital. All included patients underwent IUI treatments with letrozole+human menopausal gonadotropin (LE+hMG) for ovarian stimulation. The pregnancy outcomes were not associated with the attempts of failed OI cycles previously. Specifically, the clinical pregnancy rate was 21.14% for PCOS patients without previous OI cycles, 21.95% for PCOS patients with 1-2 previous OI cycles and 23.64% for PCOS patients with 3 or more previous OI cycles (p=0.507). The corresponding live birth rate was 16.64%, 18.06%, and 18.68%, respectively, of which the difference was not statistically significant (p=0.627). The cumulative rate per patient was 38.59% for clinical pregnancy and 31.03% for live birth, and approximately 98% of the pregnancies occurred in the first 3 cycles of IUI. PCOS women with different attempts of OI cycles had similar pregnancy outcomes after IUI, thus a history of repeated failures of OI treatments was not a predictive factor for the pregnancy outcomes in IUI cycles. Most pregnancies occurred in the first three cycles of IUI, so we strongly recommended three attempts of IUI for PCOS women before they switched to IVF/ICSI. Generally, IUI might be an assist for infertile women with PCOS before IVF/ICSI and might accelerate pregnancy for target women without invasive manipulations.