[machine-translated-for-iweto] Do children born after intracytoplasmatische sperm injection (ICSI) an increased risk of cardio

Project Details

Description

Background
Intracytoplasmic Sperm Injection (ICSI) was first described in 1991 by the Centre of Reproductive Medicine of the University of Brussels. This technique (injection of sperm directly into the oocyt) made it possible for previously infertile men to become the genetic father of their offspring. ICSI is indeed a more invasive technique than the previously widely used in vitro fertilization (IVF). Concerns about the safety for the offspring with the use of possibly impaired spermatozoa still remain. In this perspective, a large-scale follow-up study was set up since the introduction of ICSI in 1991. The goals of this follow-up project were to assess the safety of the technique in this worldwide biggest cohort of children and to inform future parents about the risks for their offspring. Data on pregnancy, prenatal diagnosis, neonatal complications, congenital malformations and psychomotor development were published in several important jounals (Bonduelle et al., 2002a,b; 2003a,b) and communicated at several international congresses. Childhood development was initially assessed at 5 years through a multi-center study where ICSI children were compared with IVF and spontaneously conceived (SC) children. This large-scale study was finanzed by the Bertarelli foundation and by the European Union since more than 1500 children divided over 5 countries participated. Later, at the age of 8 and 10 years, further childhood development and initial pubertal stages were studied in a long-term follow-up project granted by the FWO. But important questions about future health and fertility are unanswered today.

Aim
The aim of the project is to investigate whether children conceived by intracytoplasmic sperm injection (ICSI) are at increased risk of cardiovascular disease or altered sexual maturation?

Hypothesis
1. The early environment of children born after artificial reproductive technology (ART) differs in several ways from that of spontaneously conceived children. Children born after ART have an increased risk of low birth weight and dysmaturity, unrelated to maternal risk factors or pregnancy complications. It is however not clear which factors underlie this observation (genetic background and infertility per se, versus environmental conditions such as hormonal stimulation, epigenetic factors, in vitro culture, early maternal hormonal/metabolic factors). Besides altered fetal growth, a number of indirect indications from animal studies show that ART can lead to an unfavorable profile for cardiovascular risk (Rerat et al., 2005; Kwong et al., 2005).
Our own observations showed a 5 mmHg higher systolic and diastolic blood pressure measured in 8 year-old ICSI children (Belva et al., 2007). Therefore we hypothesise that children born after ART (in IVF as well as in ICSI) could have a higher risk for cardiovascular disease.
2. The importance of the genetic origin of the infertility in males treated by ICSI has not been fully investigated since the eldest children (born after ICSI) are reaching 14 years. It is however clear that a number of these children will inherit the infertility problem from their father as is shown for Yq microdeletions (Vogt et al., 1996) and for a number of genes implicated in spermatogenesis. Our hypothesis is that children born after ICSI have a higher risk of abnormal spermatogenesis and will have early detectable markers of infertility.


Objectives
1.To evaluate whether children conceived by ICSI are at increased risk of cardiovascular disease at adult age, by measuring biomarkers of cardiovascular risk
2.To evaluate whether children conceived by ICSI have alterations in sexual maturation or reproductive endocrine function

Design
The evaluation of cardiovascular risk factors will be conducted in parallel in 3 studygroups. Two groups will be studied at the age of 14-15 years and another will be studied in the neonatal period.
At the age of 14-15 years 300 singleton ICSI children will be investigated. These children are part of the worldwide eldest prospectively followed cohort since birth. Another 300 singletons, but born after spontaneous conception (SC) will be recruited from schools. Matching of those two studygroups will be based on maternal characteristics (maternal age, educational level, socio-economic status and parity) and on the age of the child. Information will be gathered from a medical examination performed by a paediatrician and from questionnaires on the childhood history filled out by the parents, replenished with data from the nationally organized medical examinations at determined visiting moments. Saliva samples will be collected from ICSI children as well as from SC children. Due to ethical considerations, we will not be able to obtain blood samples from the 2 14-year old study groups. We try to collect blood samples, after informed consent, in the 14 years-old ICSI boys. In order to nonetheless gain access to information on biomarkers of cardiovascular risk in blood (including information on lipid profile and glucose/insulin metabolism) we will carry out part of the study in cord blood samples of 60 singleton ICSI newborns and 60 SC neonates born at our hospital.

Methodology
To investigate if children born after an in vitro procedure are at increased risk for cardiovascular diseases, we are focusing on certain biomarkers that are al known to show "tracking" since childhood age.
U1.Blood pressureU at childhood's age will predict accurately adult blood pressure (Fuentes RM et al 2002). Many studies have shown the negative relationship between birth weight and adult systolic blood pressure (Huxley RR et al 2000). Blood pressure will be measured in both ICSI and SC groups,at rest in a standardised way. We will also explore if the increase in blood pressure after stress (performing the Stroop color/word conflict test; Painter et al 2006) is more pronounced in the ICSI group than in the SC group. The increase of blood pressure after stress is indeed a predictor of hypertension and coronary heart disease at adult age (Kamarck et al 1997; Jennings et al 2004). The sample size of 300 ICSI children and 300 SC children is sufficient to, with a power of 80% (alpha=0.05 two-sided) detect a difference in blood pressure of 1.5 mmHg. In a multiple regression model, correction can be made for possible confounders such as maternal age, body dimensions and gender.
U2. Abdominal body fat depositionU Besides measuring height and weight, we will also measure abdominal and hip circumference .From the measurement of skin folds, we will calculate the body fat percentage and distribution.
U3.Growth patternsU.
From the collected data (from our previous prospective studies and from national health care data of Kind and Gezin) replenished with data from follow-up studies at the age of 8 and 10 years, we will also analyse growth patterns. Especially adiposity rebound, defined as the age at which minimal body mass index (BMI) is achieved will be calculated and compared between ICSI and SC children. Early adiposity rebound predicts obesity, type 2 diabetes and coronary heart disease at later age (Barker et al 2002). Sex stratified regression will allow us to correct for possible confounders, we can detect with a power of 80% (alpha=0.05 two-sided) a difference of 9-10 months in adiposity rebound. Furthermore we can by means of mixed model analysis (height, weight, BMI) compare the childhood growth patterns of ICSI and SC children. By applying this model, we can find out if ICSI children show an increased weight gain during the first two years of their life compared with SC children, which is known to be associated with increased risk for cardiovascular disease at later age (Ekelund et al., 2007). The risk of coronary events was also indeed more strongly related to the rate of childhood gain in BMI than to the BMI attained at any particular age (Barker DJ et al 2005).
U4.Lipid profile, insuline/glucose metabolism and leptin Uwill be measured on cord blood samples of 60 ICSI children and 60 children born after SC.
U5.Sex hormones and sexual maturation
At the age of 14-15 years we will score Tanner pubertal stadia and time of menarche will be asked. In the two studygroups we will collect saliva samples for measurement of testosteron. By measuring InhibinB, a marker for spermatogenesis, in the ICSI boys, we try to gain information about their fertility status in line with our previous measurements of InhibinB at the age of 8 and 10 years (Kumanov et al., 2006).

Timing
During the first 3 years 8 months (1/1/2008-31/08/2011) the two study groups will be recruited and tested. The last four months (1/9/2011-31/12/2011) will be used to analyse the data and to report the results. Outcome measures of the data-analysis will be differences in blood pressure, in metabolic and endocrine parameters and also differences in growth and sexual maturation.

Impact of the study
In Western countries ART accounts for more than 5% of the births (ICMART, 2006). Because of this rapidly expanding population, it is important to investigate if these children have an increased risk of developing of cardiovascular/metabolic diseases or future fertility problems in order to set up prevention and information programmes.
AcronymFWOAL472
StatusFinished
Effective start/end date1/01/0831/12/11

Keywords

  • health

Flemish discipline codes

  • Basic sciences