Study question Does mode of conception such as in-vitro fertilisation (IVF), ovulation induction (OI), intra-uterine insemination (IUI) affect singleton pregnancy outcomes when compared to spontaneous conception (SC)? Summary answer Singleton pregnancies resulting from OI, IUI, IVF are associated with higher risks of adverse pregnancy outcomes compared to spontaneous pregnancies. What is known already Several meta-analysis have shown singleton pregnancies resulting from IVF have adverse pregnancy outcomes However, these studies had much smaller sample size and did not compare OI or IUI to SC. Additionally, when matched studies were analysed, the pooled events used were not adjust for medical conditions such as polycystic ovaries (PCO) and chronic hypertension which predispose patients to gestational diabetes(GDM) and pre-eclampsia (PET).he lack of consensus on how PET and GDM was defined was also a cause of bias. Our study is the largest meta-analysis to date and aims to provide clinician with the latest evidence when offering fertility treatment. Study design, size, duration Literature search in MEDLINE, COCHRANE Library, and Scopus was performed, up to November 2021. Randomised controlled trials (RCTs), non-randomised studies, cohort and case control studies, reporting on any association between pregnancy outcome, such as pre-eclampsia (PET), gestational diabetes mellitus (GDM), preterm birth, (<37 weeks (TB), very preterm birth , (<32 weeks (vVPTB), low birthweight (<2500g,LBW), very low birth weight (<1500g,VLBW) and small gestational age (SGA) in relation to mode of conception were included. Participants/materials, setting, methods 110 studies consisting of 31 cohort studies and 79 case control were included comprising a total of 32,463,058spontaneous singleton conception compared to 1,191,963 singleton pregnancies following OI, IUI and IVF treatment .Matching criteria used for adjustment were also identified For PET and GDM, only studies which defined the condition according to international agreed consensus were included Any inconsistency between studies was quantified through Higgins’ Chi-square (Chi2) and I-squared (I2) using statistical software R. Main results and the role of chance Singleton pregnancies following, OI, IUI, or IVF had a higher odds of PET compared to SC (odds ratio [OR]1.95,, 95% confidence interval [CI]1.61-2.31; I2=97%), OR 1.53, 95%CI 1.36 -1.71,, I2=84% and OR1.62, 95%CI 0.94-2.78, I2=11%).respectively. For GDM, pregnancies following, OI, IUI, or IVF had a higher odds compared to SC (OR1.59, 95%CI 1.59 -1.71, I2=83%, OR 1.62, 95%CI 0.94-2.78, I2=11% and OR1.72, 95% CI 1.49–1.98; I2=13%). Higher odds of TB and vPTB were seen in pregnancies following OI and IVF compared to SC (PTB: OR1.80, 95% CI 1.76–1.85; I2=94% and , (OR 1.47, 95% CI 1.22-1.77 I2=66% and vPTB OR 2.92, 95% CI 2.76-3.09; I2=91%). Only one study reported PTB when comparing IUI to SC (OR 1.88, 95% CI 1.40-2.53) and comparing vPTB in OI vs SC (OR 1.73 95% CI 0.71-4.18). Singleton pregnancies following, OI or IVF had a higher odds of LBW and vLBW compared to SC (OR1.98, 95% CI 1.93–2.04; I2=96%),OR1.72, 95% CI 1.49–1.98 I2=13% and OR4.57, 95% CI 4.34–4.81; I2=98% and OR2.32, 95% CI 1.60–3.37; I2=56% respectively. The rate of SGA was comparable in IVF (OR 0.91, 95% CI 0.90–0.93; I2=99%), OI (OR 0.96, 95% CI 0.95-0.97; I2=100%) and IUI (RR 0.92, 95% CI 0.90–0.94; I2=31%). Limitations, reasons for caution In cases of PE and GDM, published definitions differed in various studies and there was limited information given past medical history which increase the risk of such conditions. This made it impossible to separate the baseline confounders which may increase the risk of PE and consequently PTB, SGA and LBW. Wider implications of the findings Our meta-analysis confirmed that IVF/ICSI pregnancies are at higher odds of adverse pregnancy outcomes. This is the largest systematic review to date analysing pregnancy outcomes and mode of conception comparing OI, IUI and IVF respectively. It provides the latest evidence possible for clinicians to choose the safest fertility treatment, Trial registration number Not applicable
Study question What is the relative effectiveness and safety of final oocyte maturation trigger protocols in women undergoing in vitro fertilisation (IVF) treatment? Summary answer OHSS rate was lowest with GnRH agonist trigger and no difference in LBR was observed comparing various trigger protocols in normal, high and poor responders. What is known already Oocyte maturation trigger prior to oocyte retrieval is a crucial component of ovarian stimulation(OS). Pituitary suppression is an important component of OS in IVF, involving the use of GnRH analogues. Currently, the GnRH antagonist regimen is predominantly used given its comparable efficacy and lower risk of OHSS compared with GnRH agonist (GnRHa) regimens. Whilst only hCG trigger can be used with GnRH agonist regimens, GnRH antagonist regimen enables use of hCG trigger, GnRH agonist trigger or combinations of both as dual or double trigger. However, there is no consensus on how these trigger protocols compare in their effectiveness and safety. Study design, size, duration The following databases were searched until August 2022: MEDLINE, EMBASE, CINAHL, CENTRAL and ClinicalTrials.gov. Randomised controlled trials (RCTs) comparing at least two trigger protocols: hCG trigger, GnRH agonist trigger, dual trigger (hCG and GnRH agonist administered at the same time) and double trigger (GnRH agonist followed by hCG after a time interval) with the antagonist regimen were included. Primary outcome was live birth (LBR) per participant. Secondary outcomes included number of oocytes and OHSS rates. Participants/materials, setting, methods Two reviewers independently screened, selected studies and extracted data. Pairwise and network meta-analyses (NMA) were conducted according to ovarian response groups (normal, high and poor response). Effect estimates were presented as weighted means difference (WMD) and risk ratio (RR) with 95% confidence interval (CI) for continuous and dichotomous outcomes respectively. Quality assessment was performed using GRADE Main results and the role of chance Initial searches identified 4225 studies, of which 54 RCTs involving 5838 women met the inclusion criteria to be included in the analysis. In normal responders, there is no difference in LBR with the GnRHa vs hCG (RR:1.11,95%CI:0.83-1.49;3 studies,430 women,I2=33%,low-certainty evidence, direct comparison(DC)),dual trigger vs hCG(RR:1.14,95%CI:0.99-1.31;4 studies,1007 women,I2=33%,low-certainty evidence, DC),double trigger vs hCG(RR:0.53, 95%CI:0.27-1.06;indirect comparison(IC)),dual vs GnRHa (RR:0.97, 95%CI:0.70-1.34, IC),double vs GnRHa (RR:2.07, 95%CI:0.98-4.38, IC),dual vs double (RR:2.14, 95%CI:1.06-4.32;IC). In high responders, there is no difference in LBR with the GnRHa vs hCG (RR:1.04, 95%CI:0.84-1.29; 3 studies,178 women, I2 = 44%, low-certainty evidence, DC, dual trigger vs hCG (RR:1.82, 95%CI:1.25-2.67; 4 studies,117 women, I2 = 37%, low-certainty evidence, DC), double trigger vs hCG (RR:2.10, 95%CI:1.29-3.43, IC), dual vs GnRHa (RR:0.57, 95%CI:0.37-0.88, IC),double vs GnRHa (RR:0.49,95%CI:0.29-0.88, IC),dual vs double (RR:0.87, 95%CI:0.64-1.18; 1 study,57 women, low-certainty evidence,DC). In poor responders, there may be a difference in LBR when comparing dual trigger to hCG (RR:1.12,95%CI:1.12-2.89 1 study,112 women,low-certainty evidence,DC). OHSS rates were lowest with the use of GnRHa in high responders (RR:0.39,95%CI:0.04-3.78;9 studies;960 women;I2 =43%, low-certainty evidence,DC) and normal responders (RR:0.88, 95%CI:0.78 to 0.99;7 studies; 2246 women; I2=0%, low-certainty evidence,DC). There was no significant difference in number of oocytes or miscarriage risks with the use of any triggers. Limitations, reasons for caution Stratifying results by predicted ovarian response resulted in disconnected networks, limiting our ability to perform NMA for certain groups and outcomes. The certainty of the evidence was limited by high risk of bias. Wider implications of the findings Our results suggest that the use of short GnRH agonist trigger results in reduced OHSS rates in women with predicted normal or high ovarian response. There is no difference in LBR and number of oocytes comparing the different trigger protocols in all response groups (normal, high, poor responders) Trial registration number Not applicable
Study question Does COVID-19 vaccination (mRNA or viral vector) in women affect outcomes following IVF treatment? Summary answer There was no difference in both pre-clinical and IVF clinical outcomes in women who received vaccination (1 or 2 doses) compared to those unvaccinated. What is known already The COVID-19 vaccination rollout has been unprecedented and commenced in the UK in December 2020. Compared to the general population, pregnant women have higher risk of morbidity following COVID-19 infection. There is a drive by public health authorities for women of reproductive age to be vaccinated. However, there has been hesitancy in the uptake of vaccination amongst certain patient populations including those who are trying to conceive. Emerging data has shown that follicular function is unaffected by COVID-19 vaccination, although this data is limited. IVF treatment is unique as we can evaluate both pre-clinical embryological outcomes and clinical outcomes. Study design, size, duration We conducted a retrospective analysis of 474 women undergoing IVF treatment between Jan and Dec 2021. COVID-19 vaccination status was recorded including: vaccination type, number of vaccine doses, and whether they had previously contracted COVID-19. We recorded pre-clinical and clinical outcomes: such as number of oocytes retrieved, fertilisation rate and clinical pregnancy. Participants/materials, setting, methods Women were categorised in the three cohorts- unvaccinated (Group 1), defined as the reference group, women who had first dose of COVID-19 vaccine (Group 2) and patients who had two doses of the vaccine (Group 3). Patients whose vaccination status were not known were excluded. Statistical analysis was performed through STATA software. Outcomes were modelled with multivariable logistic and negative binomial regressions and adjusted for the following confounders: age, BMI, parity and past COVID-19 infection. Main results and the role of chance Data from women was analysed, 22.6 % had completed 2 doses, 9.5 % had one vaccine and 9.7% were unvaccinated. Among these women 24.7% had previous COVID-19 infection prior to their IVF cycle. The median number of oocytes retrieved for the entire cohort collected was 10.0 (inter-quartile range (IQR) 6.0, 14.0). There was no significant difference in the number of oocytes retrieved between women who had 1 vaccination dose, 2 doses compared to unvaccinated women (Incidence rate ratios (IRR) 1.18, 95% Confidence Interval (CI) [0.93,1.50] and 0.94, 95% CI [0.76,1.15] respectively). There was no significance difference in the fertilisation rate between women who had one vaccination dose, 2 doses and unvaccinated women (IRR)1.02, 95% CI [0.83, 1.24] and 1.11 95% CI [0.93, 1.31] or failed fertiisation rates (Odds ratio (OR) 0.74, 95% CI [0.09, 6.09] and 0.71, 95% CI [0.12, 4.18]. With regards to clinical outcomes, 51.7% of the cohort had a positive urine pregnancy test. There was no significant difference in clinical pregnancy rate between women who had first vaccination dose and those who had both doses compared to unvaccinated women (OR 3.06, 95% CI [0.37, 3.68] & OR 1.7, 95% CI [ 0.64, 4.52] respectively). Limitations, reasons for caution This is a retrospective study and further accumulated data is warranted to validate the findings. Many patients at the time of analysis were still pregnant, hence we await live birth outcomes. Wider implications of the findings This is the first study to analyse the impact of COVID-19 vaccination on IVF outcomes. These initial findings are reassuring to patients and fertility clinicians on the safety of vaccination. Trial registration number not applicable
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