Obstetric and perinatal outcomes of singleton pregnancies after blastocyst-stage embryo transfer compared with those after cleavage-stage embryo transfer: a systematic review and cumulative meta-analysis
Authors: Marconi Nicola , Allen Christopher Patrick , Bhattacharya Siladitya , Maheshwari Abha 
Published: November 2021

Abstract

BACKGROUND
Extended embryo culture to blastocyst stage is widely used in IVF and is the default strategy in most clinics. The last decade has witnessed a growing interest in obstetric–perinatal outcomes following blastocyst transfer. Recent studies have challenged the conclusions of systematic reviews that associate risks of preterm birth (PTB) and large for gestational age (LGA) babies with blastocyst transfer. A higher proportion of blastocysts is transferred as frozen-thawed embryos, which may also have added implications.

OBJECTIVE AND RATIONALE
The aim of this study was to conduct an updated systematic review of the obstetric–perinatal outcomes in singleton pregnancies following blastocyst-stage transfer compared to cleavage-stage transfer in IVF/ICSI cycles. Where deemed appropriate, data were combined in cumulative meta-analyses.

SEARCH METHODS
Data sources from Medline, EMBASE, CINAHL, Web of Science, the Cochrane Central Register of Clinical Trials and the International Clinical Trials Registry Platform (ICTRP) (1980–2020) were searched using combinations of relevant keywords. Searches had no language restrictions and were limited to human studies. Observational studies and randomized controlled trials comparing obstetric–perinatal outcomes between singleton pregnancies after blastocyst-stage transfer and those after cleavage-stage transfer in IVF/ICSI cycles were sought. Two independent reviewers extracted data in 2 × 2 tables and assessed the methodological quality of the relevant studies using the Critical Appraisal Skills Programme scoring. Cumulative meta-analyses were carried out with independent analysis of pregnancies after fresh and frozen embryo transfers, using the Comprehensive Meta-Analysis software. If provided by included studies, adjusted effect sizes were combined in a sensitivity analysis.

OUTCOMES
A total of 35 studies were included (n = 520 769 singleton pregnancies). Outcome data suggest singleton pregnancies following fresh blastocyst transfer were associated with higher risk of LGA (risk ratio (RR) 1.14; 95% CI 1.05–1.24) and very PTB (RR 1.17; 95% CI 1.08–1.26) compared to fresh cleavage-stage transfer. Singleton pregnancies following frozen blastocyst transfer were associated with higher risks of LGA (RR 1.17; 95% CI 1.08–1.27), PTB (RR 1.13; 95% CI 1.03–1.24) and caesarean section (RR 1.08; 95% CI 1.03–1.13) but lower risks of small for gestational age (RR 0.84, 95% CI 0.74–0.95) and perinatal mortality (RR 0.70; 95% CI 0.58–0.86). Increased risks of LGA and PTB after frozen blastocyst transfer persisted in the sensitivity analysis, which also showed a significantly increased risk of PTB after fresh blastocyst transfer. Cumulative meta-analyses revealed consistency in prevalence and magnitude of risks for a number of years. Data on other perinatal outcomes are still evolving.

WIDER IMPLICATIONS
While the available evidence is predominantly reassuring in the context of blastocyst-stage embryo transfer, observational data suggest that blastocyst transfer is associated with a higher risk of LGA. This holds true irrespective of fresh or frozen transfer. Meta-analysis of adjusted data showed an increased risk of PTB with fresh and frozen blastocyst transfer. However, the quality of available evidence ranges from low to very low. Although blastocyst-stage embryo transfer remains the default position in most centres, based on individual risk profile we may need to consider cleavage-stage embryo transfer in some to mitigate the risk of LGA/PTB.