Medically assisted reproduction and the risk of being born small and very small for gestational age: Assessing prematurity status as an effect modifier

Over the last decade, the use of medically assisted reproduction (MAR) has steadily increased but controversy remains with regards to its risks. We aimed to quantify the risk of being born small for gestational age (SGA) and very SGA (VSGA) associated with MARs overall and by type, namely ovarian stimulators (OS) and assisted reproductive technology (ART). We conducted a cohort study within the Quebec Pregnancy Cohort. Pregnancies coinciding with Quebec's MAR reimbursement PROGRAM period (2010-2014) with a singleton liveborn were considered. MAR was first defined dichotomously, using spontaneous conception as the reference, and categorized into three subgroups: OS alone (categorized as clomiphene and non-clomiphene OS), ART, OS/ART combined. SGA was defined as being born with a birth weight below the 10th percentile based on sex and gestational age (GA), estimated using populational curves in Canada, while VSGA was defined as being born with a birth weight below the 3rd percentile. We then estimated odds ratios (OR) for the association between MAR and SGA as well as VSGA using generalized estimated equation (GEE) models, adjusted for potential confounders (aOR). Two independent models were conducted considering MAR exposure overall, and MAR subgroup categories, using spontaneous conceptions as the reference. The impact of prematurity status (less than 37 weeks gestation) as an effect modifier in these associations was assessed by evaluating them among term and preterm pregnancies separately. A total of 57,631 pregnancies met inclusion criteria and were considered. During the study period, 2,062 women were exposed to MARs: 420 to OS alone, 557 to ART, and 1,085 to OS/ART combined. While no association was observed between MAR and SGA nor VSGA in the study population, MAR was associated with an increased risk for SGA (aOR 1.69, 95% CI 1.08-2.66; 25 exposed cases) among preterm pregnancies; no increased risk of SGA was observed in term pregnancies. MARs are known to increase the risk of preterm birth and our results further confirm that they also increase the risk of SGA among preterm pregnancies.