Long-term gastrointestinal morbidity among twins conceived by assisted reproductive technology

Abstract

Background: Assisted reproductive technologies (ART) increased the incidence of multiple pregnancies, which has a negative effect on offspring health outcomes. The long-term health outcomes for singletons born after ART is well studied, however, studies on ART twin's long-term morbidities are scarce.

Objective: This study aimed to investigate a possible association between ART resulting in twin pregnancy and long-term gastrointestinal (GI) morbidity of the offspring.

Study design: A population-based cohort study was performed in a tertiary medical center including twin deliveries born between 1991-2021. Long-term GI morbidities among twins conceived via ART including ovulation induction (OI) and in-vitro fertilization (IVF) were compared with twins born following spontaneous pregnancies. The diagnoses of GI morbidities were defined based on ICD-9 codes as recorded in community clinics and hospitalization files. A Kaplan-Meier survival curve was used to compare the cumulative incidence of GI morbidity among the study group and a Cox proportional hazards model was constructed to control for possible confounders.

Results: A total of 7,790 twins met the inclusion criteria: 2,076 twins (26.6 %) were conceived by ART. The total GI morbidity rate was significantly higher in twins conceived by ART as compared with twins from spontaneous pregnancies (34.9 % for IVF, 34.3 % for OI and 27.0 % for spontaneous twins, p < 0.001). In addition, the cumulative incidence of GI morbidity over time was elevated for twins conceived by ART (log-rank test, p < 0.001). The Cox model, controlling for confounders such as maternal age, gestational age, hypertensive disorders and diabetes mellitus found that using ART resulting in twin pregnancy is an independent risk factor for long-term GI morbidity of twin offspring (adjusted hazards ratio (aHR) for IVF vs. spontaneous = 1.42 (95 %CI 1.27-1.58, p < 0.001; aHR for OI vs spontaneous = 1.38 (95 %CI 1.20-1.60, p < 0.001).

Conclusion: In our cohort, twins conceived by ART exhibited a higher risk for long-term GI morbidity compared with spontaneously conceived twins. This association remained after adjustment for confounders although part of the increased risk may be mediated by perinatal complications such as prematurity and cesarean delivery.

Keywords: Assisted Reproductive Technology (ART); Colonic disorders, Epigenetic modifications; Gastroduodenal disorders; Gastrointestinal morbidity; In-vitro fertilization (IVF); Ovulation induction (OI); Preterm birth; Twins.