Long term consequences of in vitro fertilization and intracytoplasmic sperm injection

July 2002

Introduction

Many thousands of children have been born from assisted reproductive technology. In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are two techniques used. The oldest IVF baby, Louise Brown, is now 24 years old. Most early ICSI programmes began in 1994-5, so the eldest ICSI children are only 7-8 years old.

How safe are these procedures? Doubts have been, and continue to be, raised about the outcomes for children who are born.1,2,3,4,5 There are few follow-up studies on outcomes after pregnancy is established, or on long-term health consequences for mothers and babies.6

What is currently known

IVF exposes embryos to hazards not normally encountered in a normal pregnancy. We already know, thanks to many epidemiological studies, that events before birth can have disease outcomes in adulthood.7 But IVF is a relatively recent technology. It has been practiced widely without comprehensive assessment of its efficacy and safety.

IVF has been used for many years in veterinary science. There have been unforeseen consequences in cattle, such as the 'large offspring' syndrome.8 IVF in animals has been associated with miscarriage, very high birthrate, physical abnormalities and peri-natal mortality.9 Slight hormone and nutrient imbalances within the first week of embryonic development may alter the course of development throughout the life of IVF animals, regardless of how they appear at birth.10

In humans, IVF results in more pregnancies of multiple gestation because usually more than one embryo is placed into the uterus. Twins and triplets tend to have a lower birthweight than singleton pregnancies. But babies from single IVF pregnancies also have below-normal birth-weight.11 There is also evidence that the in vitro environment of eggs and sperm can affect subsequent embryonic and fetal development.12

Some examples of research suggesting the danger of IVF to children are:

  • Male IVF babies had a five-fold increased risk of hypospadias.13,14
  • In Finland, IVF singletons and multiples had poorer health than other infants; 25% were preterm or weighed less than 2500g.15
  • In Sweden, 5680 IVF children were studied. The most common neurological diagnosis was cerebral palsy; IVF children had increased risk of 3.7 (singletons 2.8). Suspected developmental delay was increased four-fold.16

ICSI is a particular IVF technique, used for severe male infertility. ICSI bypasses natural selection of sperm (eliminates competition) because only one sperm is used. There is no suitable animal model (an infertile primate) available, so the safety of ICSI could not be assessed on animal models before introduction.17

The following concerns have arisen:18

  1. The risks of using sperm that potentially carry genetic abnormalities; it is thought that males eligible for ICSI carry a higher rate of genetic defects.
  2. The risks of using sperm with structural defects: although there is no absolute evidence that a physically abnormal sperm has abnormal genes, these sperm would not normally be able to fertilise an egg.
  3. The potential for damage (eg. from the needle or the chemicals used in the procedure), especially damage to the chromosomes.
  4. the risk of introducing foreign material into the oocyte: some culture media may contain heavy metals known to be toxic to sperm.
Some examples of research describing health problems for ICSI-conceived children:
  • Increased prevalence of sex chromosome anomalies and a high prevalence of structural and numerical chromosomal aberrations have been reported.19
  • Infants born after ICSI were twice as likely as naturally conceived infants to have a major birth defect, and nearly 50% more likely to have a minor defect. Secondary analysis (interpret with caution) found an excess of major cardiovascular defects (odds ratio 3.99), genitourinary defects (1.33), and gastrointestinal defects (1.84) in particular cleft palate (1.33) and diaphragmatic hernia (7.73).20
  • Infants conceived through ICSI or IVF have twice the risk of a major birth defect as naturally conceived infants.21
  • ICSI offspring are at risk of also being infertile.22

Ethical analysis

Currently clinics deal with such knowledge by counselling and routinely offering prenatal genetic diagnosis.23 An abnormal result from prenatal testing is likely to culminate in abortion. Since prenatal testing is invasive, and abortion undesirable, a large amount of research has been conducted into preimplantation genetic diagnosis to detect affected embryos before they are implanted into the uterus.

But development can be affected before any defect is apparent. So an apparently normal embryo is no guarantee that foetal development and post-natal life will be normal.24

These concerns are a clear ethical challenge to clinics offering IVF. What are their ethical obligations to children born from such procedures, when doctors know there are risks involved? When IVF and ICSI children grow up, will we see lawsuits and claims for healthcare costs against doctors? What are the implications for informed consent?

IVF and ICSI can be described as an experiment on a large scale, using children as subjects. While many parents may be released from the heartbreak of infertility, the means to this end are not ethically justified.


  1. Sutcliffe AG. "Intracytoplasmic sperm injection and other aspects of new reproductive technologies" Arch Dis Child 2000; 83: 98-101 (August)
  2. McEvoy TG, et al "Large offspring syndrome and other consequences of ruminant embryo culture in vitro: relevance to blastocyst culture in human ART" Hum Fert (Camb) 2000; 3 (4): 238-246
  3. Boerjan ML, den Daas JH, Dieleman SJ "Embryonic origins of health: long-term effects of IVF in human and livestock" Theriogenology 2000 January 15; 53 (2): 537-47
  4. ibid
  5. Gissler M, Malin Silverio M, Hemminki E. "In-vitro fertilization pregnancies and perinatal health in Finland 1991-1993" Hum Reprod 1995 July; 10 (7): 1856-61
  6. Corabian P, Hailey D "The efficacy and adverse effects of in vitro fertilization and embryo transfer" Int J Technol Assess Health Care 1999 Winter; 15 (1): 66-85
  7. Van der Lende T, de Loos FA, Jorna T "Postnatal health and welfare of offspring conceived in vitro: a case for epidemiological studies" Theriogenology 2000 January 15; 53 (2): 549-54
  8. McEvoy TG et al. 2000 op cit
  9. Rieger D "Effects of the in vitro chemical environment during early embryogenesis on subsequent development" Arch Toxicol Suppl 1998; 20: 121-9
  10. Barnes FL "The effects of the early uterine environment on the subsequent development of embryo and fetus" Theriogenology 2000 January 15; 53 (2): 649-58
  11. Buitendijk SE "Children after in vitro fertilization. An overview of the literature" Int J Technol Assess Health Care 1999 Winter; 15 (1): 52-65
  12. Rieger D 1998 op cit
  13. Hypospadias: A congenital abnormality in which the male urethra fails to reach its normal termination at the end of the penis, emptying instead through an opening beneath the penis or in the perineum.
  14. Silver RI, Rodriguez R, Chang TS, Gearhart JP "In vitro fertilization is associated with an increased risk of hypospadias" J Urol 1999 June; 161 (6): 1954-7
  15. Gissler M, Malin Silverio M, Hemminki E. 1995 op cit
  16. Stromberg B et al. "Neurological sequelae in children born after in-vitro fertilisation: a population-based study" Lancet 2002 February 9; 359 (9305): 461-5
  17. Sutcliffe AG. 2000 op cit
  18. ibid
  19. Van der Westerlaken L. et al. "Invasive prenatal diagnosis after intracytoplasmic sperm injection" Fert Steril June 2001, 75 (6): 1240-1241 (survey, The Netherlands)
  20. Kurinczuk JJ and Bower C. "Birth defects in infants conceived by intracytoplasmic sperm injection: an alternative interpretation" BMJ 1997 November 15; 315 (7118): 1260-5
  21. Hansen M et al. "The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization" New England Journal of Medicine March 7 2002, 346 (10): 725-730
  22. Meschede D et al. "Clustering of male infertility in the families of couples treated with intracytoplasmic sperm injection" Hum Reprod July 2000; 15 (7): 1604-1608
  23. Van der Westerlaken L. et al. 2001 op cit
  24. Rieger D 1998 op cit