Health of ICSI children

Abstract

The introduction of IntraCytoplasmic Sperm Injection (ICSI) was a key-point in the treatment of male-factor infertility and has resulted in the birth of more than 2.5 million children worldwide.
ICSI is a more invasive technique than conventional in vitro fertilization (IVF) because one single spermatozoon is injected into the cytoplasm of one oocyte. As a result even men with impaired spermatogenesis can become the genetic father of their offspring which had not been possible before. The use of poor-quality spermatozoa and the invasiveness of the technique in combination with the essential requirement of in vitro culture and the manipulation of the gametes have raised some concern regarding the safety for the offspring born after ICSI.
Assisted conception including ICSI, differs in a number of processes from natural conception, such as ovarian hyperstimulation, manipulation of the gametes and embryo culture. Given the evidence that environmental factors, acting in the periconceptional period can have adverse effects on the health of the offspring (following the Barker hypothesis), there is concern that assisted reproduction in humans can disturb normal early developmental processes with postnatal health consequences, as has been shown in animal studies.

It has been repeatedly reported that infants born after ICSI are at risk for adverse neonatal health outcomes (increased risk of prematurity, low birth weight, congenital malformations) in comparison with the general population. At childhood ages, overall health in terms of growth, hospitalisation rate and surgery seems reassuring. However, beyond childhood and at puberty less is known about the health of these children born after ICSI.

This thesis addressed several aspects of overall health and early detectable features of sexual maturation in ICSI offspring at the ages of 8 and 14 years.

In order to evaluate the overall health of ICSI offspring, 150 ICSI singletons have been extensively medically examined at the age of 8 years and 217 ICSI singletons at the age of 14 years.
At 8 years, neurological examinations showed subtle differences between ICSI and spontaneously conceived children, but without clinical significance. Major malformations were significantly more frequent in ICSI children at age 8, but ICSI children did not require more surgery or hospitalisations in comparison with the spontaneously conceived group. Body height and body weight were not different, but a slightly higher systolic and diastolic blood pressure in ICSI conceived individuals was observed at the age of 8 years. However, 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, adiposity and its distribution, other contributors to cardiovascular disease risk were assessed at the age of 14 years. ICSI girls were at 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.

The progression through puberty was assessed clinically in males and females at the age of 8 and 14 years. Additionally, gonadal function was assessed in boys by measurement of serum inhibin B and by measurement of salivary testosterone.
At the age of 8 years, pubertal development was similar in the ICSI and the spontaneously conceived group. At the age of 14 years, pubertal development, characterized 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.

The reported findings are the first to contribute to the knowledge regarding overall health and reproductive capacity in pubertal ICSI children.
Our results are based on clinical investigations in a large group of singleton children in a tight age range at pre- and at puberty. Further, data were obtained from a homogeneous cohort of ICSI children, conceived predominantly because of male factor infertility and were compared to results from recruited controls born after spontaneous conception. Additionally to a medical examination, laboratory assessment was performed at 8 and at 14 years in order to provide a complete appraisal of the gonadal function in ICSI males.

Given that the reported results regarding overall health including cardiovascular risk and sexual maturation are novel, they should be confirmed in larger cohorts and by other centers. Nonetheless, our observations underscore the need to monitor health outcomes beyond puberty up to adult ages.

In conclusion, although overall health in terms of growth, neurological outcome, childhood disease morbidity and gonadal function seems reassuring in ICSI children up to puberty, long-term health outcomes including adiposity and hypertension in view of cardiovascular risk and reproductive capacity remain to be elucidated.

Date of Award	31 May 2012
Original language	English
Awarding Institution	Vrije Universiteit Brussel
Supervisor	Mary-Louise Bonduelle (Promotor), Jean De Schepper (Co-promotor), Herman Tournaye (Co-promotor), Christiaan Van Schravendijk (Jury), G. Verheyen (Jury), Willem Verpoest (Jury), Yvan Vandenplas (Jury), Basil Tarlatzis (Jury), Martine Cools (Jury) & Karel Hoppenbrouwers (Jury)