Fertility treatment increases the risk of preterm birth independent of multiple gestations

OBJECTIVE: To investigate the complex interplay between fertility treatment, multiple gestations, and prematurity. DESIGN: Retrospective cohort study linking the national Center for Disease Control and Prevention infant birth and death data from 2014 to 2018. SETTING: National database from Center of Disease Control and Prevention. PATIENTS: In total, 19,454,155 live-born infants with gestational ages 22–44 weeks, 114,645 infants born using non IVF fertility treatment (NIFT), and 179,960 via assisted reproductive technology (ART). INTERVENTION: Noninvasive fertility treatment or ART vs. spontaneously conceived pregnancies. MAIN OUTCOME MEASURES: The main outcome assessed was prematurity. Formal mediation analysis was conducted to calculate the percentage mediated by multiple gestations. RESULTS: Newborns born using NIFT or ART compared with those with no fertility treatment had a higher incidence of multiple gestation (no fertility treatment = 3.0%; NIFT = 24.7%; ART = 32.7%; P<.001) and prematurity (no fertility treatment = 11.2%; NIFT = 23.4%; ART = 28.4%; P<.001). Mediation analysis demonstrates that 76.8% (95% confidence interval [CI], 75.2%–78.1%) of the effect of NIFT on prematurity was mediated through multiple gestations. Similarly, 71.2% (95% CI, 70.8%–72.7%) of the effect of ART on prematurity is mediated through multiple gestation. However, the direct effect of NIFT on prematurity is 20.4% (95% CI, 19.0%–22.0%). The direct effect of ART was 24.7% (95% CI, 23.7%–25.6%). CONCLUSION: A significant proportion of prematurity associated with fertility treatment is mediated by the treatment itself, independent of multiple gestations.