Abstract
BackgroundsThe proportion of assisted reproductive technology (ART)-conceived livebirths of patients with imprinting disorders (IDs) is higher than that of the general population. Whether this is due to ART or confounding effects of advanced parental age was not investigated. We examined the association of ART and parental ages at childbirth for the development of eight epimutation-mediated imprinting disorders (epi-IDs).ResultsWe enrolled 136 patients with epi-IDs and obtained general population ART data from the Japanese robust nationwide registry. We compared the proportion of ART-conceived livebirths and maternal childbearing ages between patients with epi-IDs and the general population. The proportion of ART-conceived livebirths in patients with epi-IDs was higher than that in mothers aged ≥ 30 years, the age group in which more than 90% of ART procedures performed. The maternal childbearing ages of patients with epi-IDs were widely distributed from 19 to 45 (median: 32) within the approximate 2.5th to 97.5th percentiles of maternal childbearing ages of the general population. In addition, we compared the proportion of ART-conceived livebirths and parental ages at childbirth across patients with eight epi-IDs. We demonstrated that more than 90% of ART-conceived patients with epi-IDs were found in Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) patients, and parental ages were almost consistent in patients with eight epi-IDs, except Prader-Willi syndrome.ConclusionsAccording to the prerequisite that most of the ART procedures in Japan are performed on mothers aged ≥ 30 years, ART can be a risk factor for the development of epi-IDs, particularly SRS and BWS, for mothers aged ≥ 30 years.
Highlights
Assisted reproductive technology (ART) is widespread in developed countries [1]
Numbers of the patients with epimutation-mediated imprinting disorders (epi-imprinting disorders (IDs)) We enrolled 136 patients with epi-IDs confirmed by molecular studies as described in methods and obtained their clinical information about parental age, conception, and ART methods utilized in ART-conceived patients
According to the definition used in the Japan Society of Obstetrics and Gynecology (JSOG) database, we classified patients conceived with In vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and frozen embryo transfer (FET) as ARTconceived livebirths and patients born after Controlled ovarian stimulation (COS) only were not included in ART-conceived livebirths
Summary
Assisted reproductive technology (ART) is widespread in developed countries [1]. In Japan, 54,110 livebirths, accounting for one in 18.1 neonates, were born using ART in 2016 [2]. Cord blood and placentas from pregnancies conceived by IVF and ICSI had higher methylation levels of the PLAGL1-DMR [10] and lower methylation levels of the H19-DMR and MEST-DMR [11], respectively, compared with those from pregnancies conceived by natural conception. These studies suggested that IVF and ICSI altered the epigenetic signatures of offspring. It remains unclear whether ART procedures directly affect methylation imprints, or whether the parental issues concerned with ART, such as infertility and advanced parental age, lead to abnormal methylation. Impairment of sperm DNA methylation in male infertility and the correlation between parental advanced age at childbirth and levels of DNA methylation in the offspring have been reported [12, 13]
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