Background
Couples who have a personal or family history of a single-gene genetic disease, such as cystic fibrosis, can now undergo assisted reproductive technology (ART) to reduce the chance of them having a child with that same genetic disorder. This is known as preimplantation genetic testing for single gene disorders (PGT-M). During PGT-M, cells from a fertilised embryo are removed (biopsied) and analysed for the genetic disorder before those embryos that do not have the disorder are transferred back into the woman's uterus. The embryo cells can be biopsied at day 3 or day 5 of embryo development, with day 5 biopsy currently being the most widely used technique. Whether the embryo is biopsied at day 3 or day 5 could have different impacts on further development and implantation of the embryo, as well pregnancy and perinatal outcomes.
Key results
We found one randomised controlled trial that compared day 5 and day 3 embryo biopsy for PGT-M in a total of 20 women undergoing ART. This study did not provide enough evidence to show whether there is a difference in the chance of live birth or miscarriage; we are very uncertain about the results.
The evidence suggests that if the chance of live birth following day 3 embryo biopsy is assumed to be 40%, then the chance of live birth following day 5 biopsy is between 15% and 85%.
Evidence on other pregnancy and perinatal outcomes was poorly reported and inconclusive.
Limitations of the evidence
We have very little confidence in the evidence because we only found one small study, and the people performing the trial knew whether the women had day 3 or day 5 biopsy. This means that the results should be interpreted cautiously, and further studies are needed to confirm findings.
How up to date is this evidence?
The evidence is current to December 2021.
We are uncertain if there is a difference in live births and miscarriages, viable intrauterine pregnancies, ectopic pregnancies, stillbirths or termination of pregnancies between day 5 and day 3 embryo biopsy for PGT-M. There was insufficient evidence to draw any conclusions regarding other adverse outcomes. The results should be interpreted with caution, as the evidence was of very low certainty due to limited studies, high risk of bias in the included study, and an overall low level of precision.
Assisted reproductive technology (ART) has allowed couples with a family history of a monogenic genetic disease, or a disease-carrying gene, to reduce the chance of them having a child with the genetic disorder. This is achieved by genetically testing the embryos using an advanced process called preimplantation genetic testing for monogenic or single gene disorders (PGT-M), such as Huntington's disease or cystic fibrosis. This current terminology (PGT-M) has replaced the formerly-known preimplantation genetic diagnosis (PGD). During PGT-M, one or more embryo cells are biopsied and analysed for genetic or chromosomal anomalies before transferring the embryos to the endometrial cavity. Biopsy for PGT-M can be performed at day 3 of cleavage-stage embryo development when the embryo is at the six- to the eight-cell stage, with either one or two blastomeres being removed for analysis. Biopsy for PGT-M can also be performed on day 5 of the blastocyst stage of embryo development when the embryo has 80 to 100 cells, with five to six cells being removed for analysis. Day 5 biopsy has taken over from day 3 biopsy as the most widely-used biopsy technique; however, there is a lack of summarised evidence from randomised controlled trials (RCTs) that assesses the effectiveness and safety of day 5 biopsy compared to day 3 biopsy. Since biopsy is an invasive process, whether it is carried out at day 3 or day 5 of embryo development may have different impacts on further development, implantation, pregnancy, live birth and perinatal outcomes.
To assess the benefits and harms of day 5 embryo biopsy, in comparison to day 3 biopsy, in PGT-M in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles.
We searched the following electronic bibliographic databases in December 2021 to identify relevant RCTs: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Trials Register; CENTRAL, MEDLINE, Embase and PsycINFO. We also handsearched grey literature, such as trial registers, relevant journals, reference lists, Google Scholar, and published conference abstracts.
Eligible RCTs compared day 5 versus day 3 embryo biopsy for PGT-M.
We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live births and miscarriages. We calculated outcomes per woman/couple randomised and reported odds ratios (ORs) with 95% confidence intervals (CIs).
We included one RCT involving 20 women. The evidence was of very low certainty; the main limitations of the study were serious risk of bias due to lack of blinding of study personnel, and imprecision.
We are uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on live births (OR 1.50, 95% CI 0.26 to 8.82; 1 RCT, 20 women; very low-certainty evidence). The evidence suggests that if the chance of live birth following day 3 biopsy was assumed to be 40%, then the chance with day 5 biopsy is between 15% and 85%. It is also uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on miscarriages (OR 1.00, 95% CI 0.05 to 18.57; 1 RCT, 20 women; very low-certainty evidence).
We are uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on other secondary outcome measures, including viable intrauterine pregnancies (OR 2.25, 95% CI 0.38 to 13.47; 1 RCT, 20 women; very low-certainty evidence), ectopic pregnancies (OR 0.16, 95% CI 0.01 to 3.85; 1 RCT, 20 women; very low-certainty evidence), stillbirths (OR not estimable as no events in either group; 1 RCT, 20 women; very low-certainty evidence) or termination of pregnancies (OR 3.32, 95% CI 0.12 to 91.60; 1 RCT, 20 women; very low-certainty evidence).
No studies reported on gestational age at birth, birthweight, neonatal mortality and major congenital anomaly.