Dysmorphic features in 2-year-old IVF/ICSI offspring
Introduction
Evaluation of safety outcomes after assisted reproductive techniques (ART), like in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), remains of great concern to society as the use of ART increases continuously [1]. This is especially true as ART is known to be associated with adverse short-term outcomes, such as preterm birth, lower birth weight, perinatal mortality and increased neonatal intensive care admission [2], [3]. Furthermore, ART is associated with an increased risk of congenital abnormalities [4], [5], [6].
ART-related procedures that could interfere with developmental processes are for example the bypass of natural selection, artificial maturation of the ovum using ovarian hyperstimulation, early embryonic development in vitro, the use of culture media and the altered early intrauterine environment associated with ovarian hyperstimulation [7], [8], [9], [10], [11].
Recently Halliday et al. suggested that ovarian hyperstimulation indeed may play a role, as less blastogenesis birth defects occurred after frozen-thawed embryo transfer – a situation which is characterized by the absence of recent hormone exposure related to oocyte collection – than after fresh embryo transfer [12]. An altered early environment could result in an altered imprinting and methylation pattern of DNA after ART [13], [14], [15].
However, it is debated whether ART itself increases the risk of congenital abnormalities, or parental factors like the advanced age of couples requesting ART [16]. Increased parental age is associated with a less optimal perinatal and neurocognitive condition and more dysmorphic features in children [17], [18]. Another mediator of the increased risk of congenital abnormalities may be subfertility itself [19], [20]. The latter is suggested by the study of Ghazi et al., who reported higher rates of congenital abnormalities in a subgroup of couples who experienced a history of subfertility of at least four years [21]. Zhu et al., found that the overall prevalence of congenital abnormalities increases with increasing time to pregnancy (TTP) [22].
Most previously reported studies were unable to disentangle the contribution of assisted reproduction and that of the underlying subfertility on the risk of congenital abnormalities. Furthermore, a methodological difficulty in this type of follow-up study is the low prevalence of congenital abnormalities, implying the need of large groups. The first problem, the confounding effect of subfertility, can be minimized by using a control group composed of subfertile couples. A solution to the second problem, could be the use of minor anomalies that occur more often. Anomalies as such have limited clinical relevance, but they may nevertheless be regarded as indicators of suboptimal development [23]. For instance, it is known that a higher number of minor anomalies are associated with a higher chance of a major abnormality or malformation syndrome [24], less favorable neurodevelopmental outcome [25] and with increased risk of cancer in children [26].
The primary aim of this prospective assessor-blinded study was to examine the effects of ovarian hyperstimulation, the in vitro procedure and a combination of these two factors on the prevalence of dysmorphic features (particularly minor anomalies) with a minimal confounding effect of subfertility. To this end, we compared three groups: 1) singletons conceived with IVF or ICSI with controlled ovarian hyperstimulation (COH-IVF/ICSI), 2) singletons conceived with IVF or ICSI in the modified natural cycle (MNC-IVF/ICSI) and 3) naturally conceived singletons born to subfertile couples (Sub-NC). In COH-IVF/ICSI ovarian hyperstimulation induces the growth of multiple follicles. In MNC-IVF/ICSI no ovarian hyperstimulation is performed, so that the one follicle that naturally develops to dominance is used [27]. Therefore, comparison of COH-IVF/ICSI with MNC-IVF/ICSI children mainly reveals the effect of ovarian hyperstimulation. By comparing MNC-IVF/ICSI to Sub-NC children, we assessed the effect of the in vitro procedure.
The secondary aim was to evaluate an effect of time to pregnancy (TTP), as a proxy for the severity of subfertility, on dysmorphic features. The notion that TTP reflects the severity of subfertility is based on the finding that TTP is an important predictor of the chance of pregnancy in subfertile couples [28], [29].
Section snippets
Recruitment
This study is part of the Groningen ART cohort study, a prospective assessor-blinded longitudinal study that focuses on developmental outcome of children born following IVF and ICSI [9]. Subfertile couples with an expected date of delivery between March 2005 and December 2006 were recruited in the third trimester of pregnancy at the department of Reproductive Medicine of the University Medical Center Groningen. The singletons born to the couples formed three groups: COH-IVF/ICSI, MNC-IVF/ICSI
Participation
In the prenatal inclusion period, 89 singletons born following COH-IVF/ICSI, 79 born following MNC-IVF/ICSI, and 143 born following natural conception were invited to participate. After birth, respectively 68 (76%), 57 (72%) and 90 (63%) singletons were included. Comparison of the characteristics between the participating and non-participating group revealed that only maternal age at conception was significantly lower in non-participating Sub-NC mothers compared to participating Sub-NC mothers
Discussion
The present study suggests that ovarian hyperstimulation and the in vitro procedure itself are not associated with an increased risk of dysmorphic features, in particular minor anomalies. However, an increasing time to pregnancy is associated with a higher risk of abnormalities and clinically relevant abnormalities.
It is known from literature that IVF and ICSI are associated with an increased risk of abnormalities [4], [5], [32]. The absence of an association between IVF/ICSI and dysmorphic
Authors' roles
M.H.-A., M.J.H. and A.F.B. initiated the study. P.K., K.J.M. and J.C.v.H. collected the data. J.S., M.H.-A., M.L.H., H.E.V.-K., J.H.K. and J.M.C. interpreted the data. J.S. and M.L.H analysed the data. J.S. and M.H.-A. drafted the report. All authors commented on drafts. All authors have seen and approved the final version.
Funding
The study was financially supported by the University Medical Center Groningen, Groningen, The Netherlands, Grant number: 754510, the Postgraduate School Behavioural and Cognitive Neurosciences and the Cornelia Foundation.
Role of funding source
The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Ethics committee approval
The study design was approved by the ethics committee of the University Medical Center Groningen.
Conflicts of interest
None declared.
Acknowledgements
We thank the parents and children who participated in the study; Michiel Schrier, Linze Dijkstra and Loes de Weerd for their technical assistance. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the School for Behavioral- and Cognitive Neurosciences.
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