Maryse Bonduelle Team

Follow-up of children born after assisted reproductive technology

Medical follow-up of ICSI children

Principal Investigator: Florence Belva

Background

Since the ICSI technique (injection of sperm directly into the oocyt) 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 are a matter of debate. In this perspective, a large-scale follow-up study was set up since the introduction of ICSI in 1991. The goal of this follow-up project was to assess the safety of the technique in this worldwide biggest cohort.

Previous studies included childhood development assesment at 5 years through two large multi-center studies where ICSI children were compared with IVF and spontaneously conceived (SC) children. Both studies report reassuring results.

Later, at the age of 8 and 10 years, further psychological and medical outcomes were studied in a long-term follow-up project. ICSI and SC children show comparable cognitive and motor development until the age of 10. Physical examination including a thorough neurological examination and assessment of the pubertal maturation was comparable between ICSI and SC children, besides a higher blood pressure in ICSI offspring at the age of 8 years.

Aims

  • Since Barker's "developmental origins of adult disease" hypothesis which states that responses to environmental stimuli during critical/sensitive periods in early life may have long lasting consequences due to permanent reprogramming, specific critical windows in the prenatal period have been identified both in animals and in humans. It is however not clear if in humans IVF/ICSI can affect early embryonic development with long term consequences on cardiovascular and metabolic functioning. Therefore, we aimed to evaluate whether children conceived by ICSI are at increased risk of cardiovascular disease at older age, by mapping growth patterns and measuring biomarkers of cardiovascular risk in blood and saliva.
  • The importance of the genetic origin of the infertility in males treated by ICSI has not been fully investigated due to the young age of the offspring. It is however clear that a number of these children will inherit the infertility problem from their father. Therefore, we aimed to evaluate whether children conceived by ICSI have alterations in sexual maturation or reproductive endocrine function.

Results

In order to evaluate the overall health of ICSI offspring, 217 ICSI singletons have been extensively medically examined at the age of 14 years.

Although higher blood pressure in 8-year-old ICSI children was found previously, blood pressure in resting condition or after a stress test was not found to be increased in 14-year-old-ICSI males and females in comparison with spontaneously conceived controls, even after adjustment for current, early life and parental factors. Further, 14-year-old female but not male ICSI teenagers were found to have lower salivary cortisol concentrations in comparison with SC peers. Regarding adiposity and its distribution, ICSI girls were found to have an increased risk of central, peripheral and total adiposity. Only in ICSI boys with more advanced pubertal development, an increased risk for peripheral adiposity was found. Since particularly central adiposity is linked to adverse health outcomes later in life, continued monitoring is mandatory.

At the age of 14 years, pubertal development, characterised by menarche, genital development in males and pubic hair development in males and females was also comparable in the ICSI and the spontaneously conceived group. Breast development was less advanced in ICSI females compared with spontaneously conceived peers.

To evaluate the potential risk of testicular seminal dysfunction, serum anti-mullerian hormone (AMH) and inhibin B levels were assessed. Inhibin B, produced by the Sertoli cells of the testes and by the Sertoli cells and germinal cells during puberty, is known as a marker of spermatogenesis in adults. Normal levels of inhibin B at the age of 8 years in ICSI boys were followed by a significant increase of inhibin B levels at the age of 14 years. In addition, inhibin B levels in ICSI boys were comparable with results from peers in the general population. AMH concentrations in ICSI boys were comparable with results from boys born after spontaneous conception. Secondly, testicular function during puberty was assessed by measurement of salivary testosterone in 14-year-old ICSI boys and were found comparable with results from peers born after spontaneous conception. Reassuringly, serum inhibin B levels and salivary testosterone levels in boys from fathers with severe oligoozospermia (defined as < 5 million spermatozoa per ml) were not different from concentrations in boys from fathers without severe oligoozospermia. In order to confirm that a normal progression through subsequent stages of pubertal development occurs, resulting in a normal reproductive capacity, long-term follow-up into adulthood is required.

Currently, a follow-up study focusing on cardiometabolic risk and fertility status in 18-to 20-year old ICSI young adults is carried out at our Center.

Publications

M. Bonduelle, C. Bergh, A. Niklasson, G.D. Palermo, U.B. Wennerholm (2004) Medical follow-up of 5 year old ICSI-children. Reprod. Biomed. Online 9(1) : 91-101

M. Bonduelle, U-B. Wennerholm, B.C. Tarlatzis, S. Henriet, C. Mau, A. Victorin-Cederquist, A. Van Steirteghem, A. Balaska, J.R. Emberson and A.C. Sutcliffe (2005) A multi center cohort study of the physical health of five-year old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception. Hum. Reprod. 20: 413-419

L. Leunens, S. Celestin-Westreich, UM. BonduelleU, I. Liebaers and I. Ponjaert-Kristoffersen (2006) Cognitive and motor development of 8-year-old children born after ICSI compared to spontaneously conceived children.Hum. Reprod. 21: 2922-2929

F. Belva, S. Henriet, I. Liebaers, A.C. Van Steirteghem, S. Celestin-Westreich and M. Bonduelle (2007) Medical outcome of 8-year-old singleton ICSI children (born ? 32 weeks' gestation) and a spontaneously conceived comparison group. Hum. Reprod. 22: 506-515

L. Leunens, S. Celestin-Westreich, UM. BonduelleU, I. Liebaers and I. Ponjaert-Kristoffersen (2008) Follow-up of cognitive and motor development of 10-year-old singleton children born after ICSI compared with spontaneously conceived children. Hum. Reprod. 23: 105-111

De Schepper J, Belva F, Schiettecatte J, Anckaert E, Tournaye H, Bonduelle M. (2009) Testicular growth and tubular function in prepubertal boys conceived by intracytoplasmic sperm injection. Horm Res. 71(6): 359-63

Belva F, Bonduelle M, Painter RC, Schiettecatte J, Devroey P, De Schepper J. (2010) Serum inhibin B concentrations in pubertal boys conceived by ICSI: first results. Hum Reprod. 25(11):2811-4

Belva F, De Schrijver F, Tournaye H, Liebaers I, Devroey P, Haentjens P, Bonduelle M. (2011) Neonatal outcome of 724 children born after ICSI using non-ejaculated sperm. Hum Reprod. 26(7):1752-8

Belva F, Bonduelle M, Schiettecatte J, Tournaye H, Painter RC, Devroey P, De Schepper J. (2011) Salivary testosterone concentrations in pubertal ICSI boys compared with spontaneously conceived boys. Hum Reprod. 26(2):438-41

Belva F, Painter R, Bonduelle M, Roelants M, Devroey P, De Schepper J. (2012) Are ICSI adolescents at risk for increased adiposity? Hum Reprod. 27(1): 257-264

Belva F, Roelants M, Painter R, Bonduelle M, Devroey P, De Schepper J. (2012) Pubertal development in ICSI children. Hum Reprod 2012, Feb 10, 27:1156-1161

Belva F, Roelants M, De Schepper J, Roseboom TJ, Bonduelle M, Devroey P, Painter RC. Blood pressure in ICSI-conceived adolescents. Human Reproduction 2012 Oct;27(10):3100-8

Belva F, Painter RC, Schiettecatte J, Bonduelle M, Roelants M, Roseboom TJ, Tournaye H, De Schepper J. Gender-specific alterations in salivary cortisol levels in pubertal intracytoplasmic sperm injection offspring. Horm Res Paediatr 2012; 80:350-355

PhD theses

Onderzoek naar de lichamelijke en psychologische ontwikkeling van Intracytoplasmatische Sperma Injectie (ICSI)-kinderen door middel van individuele en gezinsdiagnostiek. Lize Leunens (2007). Promotor: S. Westreich. Copromotor: I. Kristoffersen-Ponjaert, M. Bonduelle

Health of ICSI children. Florence Belva (2012). Promotor: M Bonduelle. Co-promotor: H Tournaye, J De Schepper

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