P-767 The risk of type 1 diabetes in ART children – a Nordic cohort study on 4,589,587 liveborn children
Authors: Kyhl F , Spangsmose A.L , Gissler M , Rönö K , Romundstad L.B , Henningsen A.K.A , Bergh C , Wennerholm U.B , Opdahl S , Pinborg A 
Published: June 2022

Abstract

Study question
Do children born after assisted reproductive technology (ART) have a higher risk of type 1 diabetes (DM1) compared to non-ART children?

Summary answer
Children born after ART had similar risk of DM1 compared to non-ART children after adjusting for confounding factors.

What is known already
ART is associated with higher rates of preterm birth, low birth weight and being born small for gestational age, which are risk factors for future metabolic syndrome. Furthermore, children born after frozen embryo transfer (FET) have an increased risk of being born large for gestational age and with a high birth weight, which has been found to increase the risk of DM1. A previous study on 3,138,540 Swedish children, found no association between ART and DM1 when compared to non-ART children but found an increased risk of DM1 in children born after FET compared to fresh embryo transfer.

Study design, size, duration
A registry-based cohort study using data from Denmark (birth years 1994–2014), Finland (1990–2014) and Norway (1984–2015) including 77,920 ART-children and 4,511,667 non-ART-children. We investigated the hazard ratio for DM1. Median time to follow-up was 8.2 years (IQR 4.2–13.8) and 13.5 years (IQR 6.9–20.1) in the ART and non-ART group, respectively. Time to follow-up was defined as date of birth until date of DM1 diagnosis, emigration, death or 31st of December 2015, whichever came first.

Participants/materials, setting, methods
Data originates from a Nordic registry containing information national from ART and patient registries. DM1 was defined as the ICD-10-diagnosis (E10) or ICD-9-diagnosis (250, Finland only). Crude and adjusted hazard ratios (HR) of DM1 were assessed for ART vs. non-ART children, intracytoplasmic sperm injection (ICSI) vs. in vitro fertilization (IVF) and FET vs. fresh embryo transfer using Cox proportional hazard models by adjusting for birthweight, sex, parity, year of birth, maternal diabetes, smoking and education.

Main results and the role of chance
Overall, 261 (3.3/1000) ART; and 22,074 (4.9/1000) non-ART-children were diagnosed with DM1 within the time to follow-up. We found no increased risk of DM1 in the ART group compared to the non-ART group. The crude HR of DM1 in ART-children was 1.12 (95% CI 0.99–1.26) with non-ART-children being the reference. The adjusted HR was 0.96 (95% CI 0.83–1.11).
Since the Finnish cohort had no information on the method of ART, the following results are based on the Danish and Norwegian cohorts only. We found no association between fresh ICSI (34 cases, 2.0/1000) and DM1 compared to fresh IVF (71 cases, 2.7/1000), crude HR 1.13 (95% CI 0.74–1.71) and adjusted HR 0.90 (95% CI 0.49–1.64), fresh IVF being the reference. Furthermore, no increased risk of DM1 was found when comparing FET (cases 10, 1.4/1000) and fresh embryo transfer (cases 110, 2.4/1000). Crude HR of FET was 0.90 (95% CI 0.47–1.72), with the adjusted HR being 0.35 (95% CI 0.09–1.46), fresh embryo transfer being the reference. No assessment of HR in frozen ICSI and IVF was performed due to a limited number of cases.

Limitations, reasons for caution
The main limitation of the study is the sparse information of the parents, resulting in residual confounding. In the sub-analyses, fresh ICSI vs IVF and fresh vs FET, there is a limited number of cases with DM1. DM1 and type 2 diabetes is not differentiated in ICD-9 classifications.

Wider implications of the findings
The number of children born after ART is increasing each year and so is children diagnosed with diabetes, hence it is reassuring that the risk of DM1 does not seem to be increased in children born after ART. Our findings are important information when counselling women and men with infertility.

Trial registration number
Not applicaple