P-767 Preterm birth in singleton pregnancies conceived by in-vitro fertilization or intracytoplasmic sperm injection: a systematic review with umbrella meta-analysis
Authors: Salmeri N , Alteri A , Farina A , Pozzoni M , Viganò P , Candiani M , Cavoretto P  I 
Published: July 2024

Abstract

Study question
What is the risk level and potential etiology of preterm birth (PTB) in singleton pregnancies from in-vitro fertilization (IVF) or intra-cytoplasmic injection (ICSI)?

Summary answer
Singleton pregnancies from IVF/ICSI have, on average, double the risk of PTB compared to natural conceptions, with a higher risk for iatrogenic than spontaneous PTB.

What is known already
IVF/ICSI pregnancies are associated with a higher PTB risk, with a predominant effect mediated by the effect of multiples and a poor understanding of underlying etiology, particularly in singletons. According to the European IVF Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE), about 16% of singleton conceived through IVF/ICSI were born preterm in 2019. Considering the global a shift towards single embryo transfers (ETs), it becomes crucial to precisely determine and convey the PTB risk specific to singleton pregnancies conceived through IVF/ICSI, collecting all available evidence on supposed PTB etiology.

Study design, size, duration
A comprehensive search in major online databases was conducted up to December 31, 2023. Eligible studies were systematic reviews with quantitative data. The primary aim was to quantify PTB risk in singletons conceived by IVF/ICSI compared to natural pregnancies. Secondary objectives included assessing very preterm birth (VPTB) risk and exploring PTB’s etiology, phenotype, and initiation. PTB and VPTB were defined by the World Health Organization as delivery before 37 or 32 weeks, respectively.

Participants/materials, setting, methods
Random-effects meta-analysis models were used for pooling effect measures. Estimates were presented as odds ratios (ORs) with 95% confidence intervals (CIs). Information available on etiology, phenotype, initiation of PTB and relevant moderators was extracted and employed for subgroup analyses. The extent of overlap in the original studies was measured using the Corrected Covered Area (CCA) assessment. The quality of the included reviews was evaluated with the AMSTAR 2 tool and quality of evidence by GRADE.

Main results and the role of chance
Twelve meta-analyses with a total of 16,522,917 pregnancies were included. IVF/ICSI singletons showed a significantly higher risk of PTB compared to natural conception (PTB ˂37 weeks: OR: 1.72, 95% CI: 1.57-1.89). The pooled risk estimate was higher for births below 32 weeks (VPTB &lt;32 weeks: OR: 2.19, 95%CI: 1.82-2.64). Influential analysis reinforced the strength of this association. Subgroup analyses investigating supposed etiology revealed a comparable risk magnitude for spontaneous PTB (OR 1.79, 95% CI:1.56-2.04) and a greater risk for iatrogenic PTB (OR: 2.28, 95%CI: 1.72–3.02). PTB risk was consistent in the subgroup of conventional IVF (OR: 1.95, 95% CI: 1.76-2.15) and higher in the subgroup of fresh-only ETs (OR: 1.79, 95% CI: 1.55-2.07) compared to frozen-thawed ETs (OR: 1.39, 95%CI: 1.34-1.43). CCA assessment showed minimal study overlap (13%). The quality of the evidence by GRADE assessment was judged as low to very low.

Limitations, reasons for caution
The methodological quality of the included reviews, as rated by AMSTAR 2, was judged as low to very low. Most included studies lacked granular data on IVF/ICSI indications and on specific PTB etiology, phenotypes, or initiation.

Wider implications of the findings
The risk of PTB is about double in IVF/ICSI singleton pregnancies compared to naturally conceived, with paucity of available data on PTB aetiology, phenotype, or initiation. The greater risk increase involves iatrogenic PTB from fresh ET and VPTB, likely due to placental aetiology.

Trial registration number
PROSPERO ID: CRD42023411418