IVF/ICSI treatment and the risk of iatrogenic preterm birth in singleton pregnancies: systematic review and meta-analysis of cohort studies.

Objectives: Preterm birth (PTB) is more frequent among fertilization (IVF) as compared to natural conception and recent research in this group describes an increase of its spontaneous etiology. However, clear description and quantification of iatrogenic preterm birth (IPTB) was not determined in IVF/ICSI (intra-cytoplasmic sperm injection) conceptions. This study quantifies the risk of IPTB in singleton pregnancies resulting from IVF/ICSI as compared to spontaneous conceptions (SCs).

Methods: Web-based databases search (PubMed/Medline, Scopus, Web of Science) from inception up to January 2019 looking for cohort studies comparing the risk of IPTB in singleton pregnancies obtained with IVF/ICSI (intervention group) or SC (control group). Only studies with clear distinction of spontaneous and indicated PTB were included. Primary outcome was IPTB before 37 weeks of gestation, defined as indicated delivery for any medical recommendation. All pertinent secondary outcomes were also included: IPTB <34/32/28 weeks, abnormal cardiotocography (CTG), abruptio, placenta previa, pre-eclampsia, fetal growth restriction, any other available indication to IPTB. A meta-analysis calculated the pooled odds ratio (OR) for IPTB in IVF/ICSI and SC, using random effects model. Sensitivity analysis for study quality, methodology of case counting, use of cryotransfer, and secondary analyses for available indications of IPTB were also performed. Prospero RN: CRD42019117672.

Results: Pooled crude analysis showed a sample size of 9590 births with significant increase in IPTB <37 weeks in IVF/ICSI pregnancies (nine studies, pooled proportion IPTB IVF/ICSI 4.73% vs. SC 1.81%; OR = 2.47; 95% CI: 1.46-4.18;  = 67%). Pooled analysis was impossible for most secondary outcomes due to lack of available data and failed to show statistical significance for abnormal CTG. The risk for IPTB due to abruptio placentae or placenta previa was significantly increased in IVF/ICSI pregnancies (two studies, 561 pregnancies; pooled proportion IPTB IVF/ICSI 2.12% vs. SC 1.06%; OR = 5.41; 95% CI: 1.26-23.25; : 0%).

Conclusion: The risk of IPTB <37 weeks in singleton pregnancies achieved after IVF/ICSI is significantly greater than that occurring in SC. This is likely due to a multifactorial etiology, in which placental diseases are included. Full etiologic understanding of this association needs further clarification.

Summary: The risk of IPTB below 37 weeks in singleton pregnancies achieved after IVF/ICSI is more than double than that occurring in natural conception.