Preterm birth in singleton pregnancies conceived by in vitro fertilization or intracytoplasmic sperm injection: an overview of systematic reviews

BACKGROUND: The rate of preterm birth of singletons conceived through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is increased, being as high as 15% to 16% across Europe and the United States. However, the underlying etiology, phenotype, and mechanisms initiating preterm birth (PTB) are poorly understood. OBJECTIVE: To quantify the PTB risk and examine supposed etiology in IVF/ICSI singleton pregnancies compared to naturally conceived. STUDY DESIGN: Overview of reviews including all available systematic reviews with meta-analysis comparing PTB risk in IVF/ICSI and naturally conceived singletons. A comprehensive search of PubMed/MEDLINE, Embase, Scopus, and Cochrane Library databases was performed up to December 31, 2023. Information available on etiology, phenotype, initiation of PTB, and relevant moderators was retrieved and employed for subgroup analyses. Random-effects meta-analysis models were used for pooling effect measures. Estimates were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The extent of overlap in the original studies was measured using the corrected covered area assessment. The quality of the included reviews was evaluated with the AMSTAR 2 tool. The Grading of Recommendations Assessment, Development and Evaluation approach was applied to rate evidence certainty. The protocol was registered on PROspective Register of Systematic Reviews (CRD42023411418). RESULTS: Twelve meta-analyses (16,522,917 pregnancies; >433,330 IVF/ICSI) were included. IVF/ICSI singletons showed a significantly higher PTB risk compared to natural conception (PTB <37 weeks: OR: 1.72, 95% CI: 1.57-1.89; PTB<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 (OR: 1.79, 95% CI: 1.55-2.07) vs frozen-thawed embryo transfers (OR: 1.39, 95% CI: 1.34-1.43). There was minimal study overlap (13%). The certainty of the evidence was graded as low to very low. CONCLUSION: Singletons conceived through IVF/ICSI have a 2-fold increased risk of PTB compared to natural conception, despite the low certainty of the evidence. There is paucity of available data on PTB etiology, phenotype, or initiation. The greater risk increase is observed in fresh embryo transfers and involves iatrogenic PTB and PTB <32 weeks, likely attributable to placental etiology. Future studies should collect data on PTB etiology, phenotype, and initiation. IVF/ICSI pregnancies should undertake specialistic care with early screening for placental disorders, cervical length, and growth abnormalities, allowing appropriate timely follow-up, preventive measures, and therapeutic interventions strategies.