Luteal phase support for women trying to conceive by intrauterine insemination or sexual intercourse.

BACKGROUND: Ovulation induction may impact endometrial receptivity due to insufficient progesterone secretion. Low progesterone is associated with poor pregnancy outcomes. OBJECTIVES: To assess the effectiveness and safety of luteal phase support (LPS) in infertile women trying to conceive by intrauterine insemination or by sexual intercourse. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trial registries for ongoing trials, and reference lists of articles (from inception to 25 August 2021). SELECTION CRITERIA: Randomised controlled trials (RCTs) of LPS using progestogen, human chorionic gonadotropin (hCG), or gonadotropin-releasing hormone (GnRH) agonist supplementation in IUI or natural cycle. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were live birth rate/ongoing pregnancy rate (LBR/OPR) and miscarriage.  MAIN RESULTS: We included 25 RCTs (5111 participants). Most studies were at unclear or high risk of bias. We graded the certainty of evidence as very low to low. The main limitations of the evidence were poor reporting and imprecision. 1. Progesterone supplement versus placebo or no treatment  We are uncertain if vaginal progesterone increases LBR/OPR (risk ratio (RR) 1.10, 95% confidence interval (CI) 0.81 to 1.48; 7 RCTs; 1792 participants; low-certainty evidence) or decreases miscarriage per pregnancy compared to placebo or no treatment (RR 0.70, 95% CI 0.40 to 1.25; 5 RCTs; 261 participants). There were no data on LBR or miscarriage with oral stimulation. We are uncertain if progesterone increases LBR/OPR in women with gonadotropin stimulation (RR 1.24, 95% CI 0.80 to 1.92; 4 RCTs; 1054 participants; low-certainty evidence) and oral stimulation (clomiphene citrate or letrozole) (RR 0.97, 95% CI 0.58 to 1.64; 2 RCTs; 485 participants; low-certainty evidence). One study reported on OPR in women with gonadotropin plus oral stimulation; the evidence from this study was uncertain (RR 0.73, 95% CI 0.37 to 1.42; 1 RCT; 253 participants; low-certainty evidence). Given the low certainty of the evidence, it is unclear if progesterone reduces miscarriage per clinical pregnancy in any stimulation protocol (RR 0.68, 95% CI 0.24 to 1.91; 2 RCTs; 102 participants, with gonadotropin; RR 0.67, 95% CI 0.30 to 1.50; 2 RCTs; 123 participants, with gonadotropin plus oral stimulation; and RR 0.53, 95% CI 0.25 to 1.14; 2 RCTs; 119 participants, with oral stimulation). Low-certainty evidence suggests that progesterone in all types of ovarian stimulation may increase clinical pregnancy compared to placebo (RR 1.38, 95% CI 1.10 to 1.74; 7 RCTs; 1437 participants, with gonadotropin; RR 1.40, 95% CI 1.03 to 1.90; 4 RCTs; 733 participants, with gonadotropin plus oral stimulation (clomiphene citrate or letrozole); and RR 1.44, 95% CI 1.04 to 1.98; 6 RCTs; 1073 participants, with oral stimulation). 2. Progesterone supplementation regimen  We are uncertain if there is any difference between 300 mg and 600 mg of vaginal progesterone for OPR and multiple pregnancy (RR 1.58, 95% CI 0.81 to 3.09; 1 RCT; 200 participants; very low-certainty evidence; and RR 0.50, 95% CI 0.05 to 5.43; 1 RCT; 200 participants, very low-certainty evidence, respectively). No other outcomes were reported for this comparison. There were three different comparisons between progesterone regimens. For OPR, the evidence is very uncertain for intramuscular (IM) versus vaginal progesterone (RR 0.59, 95% CI 0.34 to 1.02; 1 RCT; 225 participants; very low-certainty evidence); we are uncertain if there is any difference between oral and vaginal progesterone (RR 1.25, 95% CI 0.70 to 2.22; 1 RCT; 150 participants; very low-certainty evidence) or between subcutaneous and vaginal progesterone (RR 1.05, 95% CI 0.54 to 2.05; 1 RCT; 246 participants; very low-certainty evidence). We are uncertain if IM or oral progesterone reduces miscarriage per clinical pregnancy compared to vaginal progesterone (RR 0.75, 95% CI 0.43 to 1.32; 1 RCT; 81 participants and RR 0.58, 95% CI 0.11 to 3.09; 1 RCT; 41 participants, respectively). Clinical pregnancy and multiple pregnancy were reported for all comparisons; the evidence for these outcomes was very uncertain. Only one RCT reported adverse effects. We are uncertain if IM route increases the risk of adverse effects when compared with the vaginal route (RR 9.25, 95% CI 2.21 to 38.78; 1 RCT; 225 participants; very low-certainty evidence). 3. GnRH agonist versus placebo or no treatment  No trials reported live birth. The evidence is very uncertain about the effect of GnRH agonist in ongoing pregnancy (RR 1.10, 95% CI 0.70 to 1.74; 1 RCT; 291 participants, very low-certainty evidence), miscarriage per clinical pregnancy (RR 0.73, 95% CI 0.26 to 2.10; 2 RCTs; 79 participants, very low-certainty evidence) and clinical pregnancy (RR 1.00, 95% CI 0.68 to 1.47; 2 RCTs; 340 participants; very low-certainty evidence), and multiple pregnancy (RR 0.28, 95% CI 0.11 to 0.70; 2 RCTs; 126 participants). 4. GnRH agonist versus vaginal progesterone  The evidence for the effect of GnRH agonist injection on clinical pregnancy is very uncertain (RR 1.00, 95% CI 0.51 to 1.95; 1 RCT; 242 participants). 5. HCG injection versus no treatment  The evidence for the effect of hCG injection on clinical pregnancy (RR 0.93, 95% CI 0.40 to 2.13; 1 RCT; 130 participants) and multiple pregnancy rates (RR 1.03, 95% CI 0.22 to 4.92; 1 RCT; 130 participants) is very uncertain. 6. Luteal support in natural cycle No study evaluated the effect of LPS in natural cycle. We could not perform sensitivity analyses, as there were no studies at low risk of selection bias and not at high risk in other domains. AUTHORS' CONCLUSIONS: We are uncertain if vaginal progesterone supplementation during luteal phase is associated with a higher live birth/ongoing pregnancy rate. Vaginal progesterone may increase clinical pregnancy rate; however, its effect on miscarriage rate and multiple pregnancy rate is uncertain. We are uncertain if IM progesterone improves ongoing pregnancy rates or decreases miscarriage rate when compared to vaginal progesterone. Regarding the other reported comparisons, neither oral progesterone nor any other medication appears to be associated with an improvement in pregnancy outcomes (very low-certainty evidence).

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction.

BACKGROUND: Subfertility is a condition found in up to 15% of couples of reproductive age. Gamete micromanipulation, such as intracytoplasmic sperm injection (ICSI), is very useful for treating couples with compromised sperm parameters. An alternative method of sperm selection has been described; the spermatozoa are selected under high magnification (over 6000x) and used for ICSI. This technique, named intracytoplasmic morphologically selected sperm injection (IMSI), has a theoretical potential to improve reproductive outcomes among couples undergoing assisted reproduction techniques (ART). However, our previous version of this Cochrane Review was unable to find evidence that supported this possible beneficial effect. This is an update of Teixeira 2013. OBJECTIVES: To identify, appraise, and summarise the available evidence regarding efficacy and safety of IMSI compared to ICSI in couples undergoing ART. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in these electronic databases: the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and in these trial registers: ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We also handsearched the reference lists of included studies and similar reviews. We performed the last electronic search on 18 November 2019. SELECTION CRITERIA: We only considered RCTs that compared ICSI and IMSI; we did not include quasi-randomised trials. We considered studies that permitted the inclusion of the same participant more than once (cross-over or per cycle trials) only if data regarding the first treatment of each participant were available. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and assessment of the risk of bias and quality of the evidence; we solved disagreements by consulting a third review author. We corresponded with study investigators to resolve any queries, as required. MAIN RESULTS: The updated search retrieved 535 records; we included 13 parallel-designed RCTs comparing IMSI and ICSI (four studies were added since the previous version), comprising 2775 couples (IMSI = 1256; ICSI = 1519). We are uncertain if IMSI improves live birth rates (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.89 to 1.39; 5 studies, 929 couples; I² = 1%), miscarriage rates per couple (RR 1.07, 95% CI 0.78 to 1.48; 10 studies, 2297 couples; I² = 0%, very-low quality evidence), and miscarriage rate per pregnancy (RR 0.90, 95% CI 0.68 to 1.20; 10 studies, 783 couples; I² = 0%, very-low quality evidence). We are uncertain if IMSI improves clinical pregnancy rates (RR 1.23, 95% CI 1.11 to 1.37; 13 studies, 2775 couples; I² = 47%, very-low quality evidence). None of the included studies reported congenital abnormalities. We judged the evidence for all outcomes to be of very low-quality. We downgraded the quality of the evidence due to limitations of the included studies (risk of bias), inconsistency of results, and a strong indication of publication bias. AUTHORS' CONCLUSIONS: The current evidence from randomised controlled trials does not support or refute the clinical use of intracytoplasmic sperm injection (intracytoplasmic morphologically selected sperm injection (IMSI). We are very uncertain of the chances of having a live birth and of the risk of having a miscarriage. We found very low-quality evidence that IMSI may increase chances of a clinical pregnancy, which means that we are still very uncertain about any real difference. We did not find any trials reporting on the risk of congenital abnormalities. Well-designed and sufficiently powered trials are still required.

Low versus atmospheric oxygen tension for embryo culture in assisted reproduction: a systematic review and meta-analysis.

OBJECTIVE: To appraise the available evidence comparing low oxygen (LowO2) and atmospheric oxygen tension (AtmO2) for embryo culture. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing assisted reproduction using embryo culture. INTERVENTION(S): Embryo culture using LowO2 versus AtmO2. MAIN OUTCOME MEASURE(S): Reproductive, laboratory, and pregnancy outcomes. RESULT(S): A total of 21 studies were included in this review. All used O2 concentration between 5% and 6% in the LowO2 group. Considering the studies that randomized women/couples, we observed very low quality evidence that LowO2 is better for live birth/ongoing pregnancy (relative risk [RR] = 1.1, 95% confidence interval [CI] 1.0-1.3) and clinical pregnancy (RR = 1.1, 95% CI 1.0-1.2). Considering the studies that randomized oocytes/embryos, we observed low quality evidence of no difference of fertilization (RR = 1.0, 95% CI 1.0-1.0) and cleavage rate (RR = 1.0, 95% CI 1.0-1.1), and low quality evidence that LowO2 is better for high/top morphology at the cleavage stage (RR = 1.2, 95% CI 1.1-1.3). No studies comparing pregnancy outcomes were identified. Several studies used different incubators in the groups-a new model for the LowO2 group and an old model for the AtmO2 group. The risk of detection bias for the laboratory outcomes was high as embryologists were not blinded. CONCLUSION(S): Although we observed a small improvement (∼5%) in live birth/ongoing pregnancy and clinical pregnancy rates (PRs), the evidence is of very low quality and the best interpretation is that we are still very uncertain about differences in this comparison. The clinical equipoise remains and more large well-conducted randomized controlled trials are needed. They should use the same incubators in both groups and the embryologists should be blinded at least when evaluating laboratory outcomes.

Melatonin supplementation during controlled ovarian stimulation for women undergoing assisted reproductive technology: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To examine the best evidence available regarding the effect of melatonin supplementation during controlled ovarian stimulation (COS) on the main assisted reproductive technology (ART) outcomes. DESIGN: Systematic review and meta-analysis of randomized clinical trials (RCT). SETTING: Not applicable. PATIENT(S): Women undergoing COS for ART. INTERVENTION(S): Melatonin supplementation during COS for women undergoing ART. MAIN OUTCOME MEASURE(S): Live birth rate, clinical pregnancy rate, number of retrieved oocytes, miscarriage rate, ovarian hyperstimulation syndrome (OHSS) rate, and number of congenital abnormalities. Comparisons were performed using risk ratio (RR) or mean difference (MD). RESULT(S): Five RCTs were considered eligible, and their data were extracted and included in a meta-analysis. No studies reported live-birth or congenital abnormalities. Our estimates were imprecise for distinguishing between no effect and benefit considering clinical pregnancy (RR, 1.21; 95% confidence interval [CI], 0.98-1.50, five studies, 680 women, low quality-evidence) and the number of oocytes retrieved (MD, 0.6; 95% CI, -0.2-2.2, five studies, 680 women, low quality-evidence). Our estimates were imprecise for distinguishing among harm, no effect, and benefit considering miscarriage (RR, 1.07; 95% CI, 0.43-2.68, two studies, 143 clinical pregnancies, low quality-evidence) and interventions to reduce the risk of OHSS (RR,1.01; 95% CI, 0.33-3.08, one study, 358 women, low quality-evidence). CONCLUSION(S): More studies investigating the role of melatonin supplementation are still needed before recommending its use in clinical practice.

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction.

BACKGROUND: Subfertility is a condition found in up to 15% of couples of reproductive age. Gamete micromanipulation, such as intracytoplasmic sperm injection (ICSI), is very useful for treating couples with compromised sperm parameters. Recently a new method of sperm selection named 'motile sperm organelle morphology examination' (MSOME) has been described and the spermatozoa selected under high magnification (over 6000x) used for ICSI. This new technique, named intracytoplasmic morphologically selected sperm injection (IMSI), has a theoretical potential to improve reproductive outcomes among couples undergoing assisted reproduction techniques (ART). OBJECTIVES: To compare the effectiveness and safety of IMSI and ICSI in couples undergoing ART. SEARCH METHODS: We searched for randomised controlled trials (RCT) in electronic databases (Cochrane Menstrual Disorders and Subfertility Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), trials registers (ClinicalTrials.gov, Current Controlled Trials, World Health Organization International Clinical Trials Registry Platform), conference abstracts (ISI Web of knowledge), and grey literature (OpenGrey); in addition, we handsearched the reference lists of included studies and similar reviews. We performed the last electronic search on 8 May 2013. SELECTION CRITERIA: We considered only truly randomised controlled trials comparing ICSI and IMSI to be eligible; we did not include quasi or pseudo-randomised trials. We included studies that permitted the inclusion of the same participant more than once (cross-over or 'per cycle' trials) only if data regarding the first treatment of each participant were available. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and assessment of the risk of bias and we solved disagreements by consulting a third review author. We corresponded with study investigators in order to resolve any queries, as required. MAIN RESULTS: The search retrieved 294 records; from those, nine parallel design studies were included, comprising 2014 couples (IMSI = 1002; ICSI = 1012). Live birth was evaluated by only one trial and there was no significant evidence of a difference between IMSI and ICSI (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.79 to 1.64, 1 RCT, 168 women, I(2) = not applicable, low-quality evidence). IMSI was associated with a significant improvement in clinical pregnancy rate (RR 1.29, 95% CI 1.07 to 1.56, 9 RCTs, 2014 women, I(2) = 57%, very-low-quality evidence). We downgraded the quality of this evidence because of imprecision, inconsistency, and strong indication of publication bias. We found no significant difference in miscarriage rate between IMSI and ICSI (RR 0.82, 95% CI 0.59 to 1.14, 6 RCTs, 552 clinical pregnancies, I(2) = 17%, very-low-quality evidence). None of the included studies reported congenital abnormalities. AUTHORS' CONCLUSIONS: Results from RCTs do not support the clinical use of IMSI. There is no evidence of effect on live birth or miscarriage and the evidence that IMSI improves clinical pregnancy is of very low quality. There is no indication that IMSI increases congenital abnormalities. Further trials are necessary to improve the evidence quality before recommending IMSI in clinical practice.

Maternal flow-mediated dilation and nitrite concentration during third trimester of pregnancy and postpartum period.

OBJECTIVES: To compare maternal flow-mediated dilation (FMD) of the brachial artery and nitrite concentration between third trimester of pregnancy (3rdT) and postpartum (PP) period. Additionally, we will evaluate whether FMD correlates with nitrite concentration in both periods. METHODS: Eligibility criteria was healthy women with singleton pregnancy, gestational age >28 weeks, nonsmokers, and no personal or family history of vascular disease. Each women was examined during 3rdT and between 8 and 12 weeks PP to evaluate FMD and nitrite concentration in whole blood. Women not examined in both periods were excluded. Values between both periods were compared using paired t tests. Correlation between FMD and nitrite was examined by Pearson correlation coefficient. Significance level set as p < 0.05. RESULTS: We invited 42 pregnant women. Among them, 35 were eligible and 7 of them were excluded for not attending the PP evaluation resulting in 28 participants analyzed. We found no significant change in FMD (10.39 ± 5.57% vs. 8.42 ± 4.21%; p = 0.11; 3rdT vs. PP, respectively) and no significant change in nitrite concentration (257.41 ± 122.95 nmol/L vs. 237.16 ± 90.01 nmol/L; p = 0.28). Baseline brachial artery diameter had a significant reduction (3.11 ± 0.30 to 2.75 ± 0.34 mm; p < 0.01). No significant correlation between FMD and nitrite during 3rdT (r = -0.13; p = 0.50) or PP (r = 0.14; p = 0.48) was found. CONCLUSIONS: We did not observe significant changes in both FMD and nitrite concentration between third trimester and the PP period. FMD did not correlate with nitrite in both periods. More studies are needed to confirm our findings.