Perinatal Risks Associated with IVF (SAC Opinion Paper 8)

Scientific Advisory Committee Opinion Paper 8

This paper can be downloaded as a pdf file:

1. Introduction

With over 25 years' experience, in vitro fertilization (IVF) is now routine medical practice in the management of infertility. It is estimated that infertility affects one in seven couples in the UK at some stage in their reproductive life. In the UK Millennium Cohort Study 18 383 mothers who delivered a baby in the year 2000 were interviewed and 2.5% reported receiving some form of fertility treatment prior to conception.1 Since the first IVF baby was born in 1978, there have been about two million IVF babies born worldwide and births following IVF account for over 1% of all births in the UK. This proportion is lower than in some other countries, probably owing to the lower IVF treatment rate in the UK compared with other European countries (UK 595, Holland 889 and Finland 1528 cycles/million population). This difference is thought to be attributable, in part, to the minimal public funding available for IVF in the UK.

The course of the pregnancy and the health of children born after IVF are two of the most important outcomes of IVF. There is a continuing debate as to whether these outcomes show poorer results compared with spontaneous conception and, if so, whether, as was initially thought to be the case, the differences are predominantly the result of a higher incidence of multiple pregnancy. The first indication that IVF singleton pregnancies may also have a poorer outcome appeared in 1985,2 although it was not clear what proportion of the difference related to the IVF procedures and what to factors such as older maternal age and parity.

It is in this context that this paper summarises the growing body of evidence concerning the outcomes of pregnancy, delivery and the early neonatal period associated with being conceived by IVF and related procedures. For these purposes, this review includes data relating to IVF and associated procedures, such as intracytoplasmic sperm injection (ICSI), blastocyst culture, assisted hatching and genetic diagnosis. However, gamete intrafallopian transfer (GIFT) or ovulation induction alone or with artificial insemination are not discussed. Unless specifically stated, the term IVF is used to encompass IVF and any laboratory procedure associated with IVF.

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2. Multiple conceptions and multiple births

Without doubt the single most significant and substantial impact on the course of any pregnancy, delivery, immediate pregnancy outcome and health of the child is whether the conception and subsequent development is as a single or multiple gestation. This is true regardless of whether conception results spontaneously or follows fertility treatment. The number of fetuses and their chorionicity are the most important predictors of outcome for multiple gestations. The risks of adverse perinatal outcomes increase disproportionately in relation to the number of fetuses. Compared with dichorionic multiples, monochorionic multiples have higher rates of adverse outcomes for all perinatal parameters.

The importance of the relationship between plurality and adverse outcomes arises in IVF because, in contrast to spontaneous conceptions, which result in multiple births in approximately one in 100 instances, about one in four of all IVF pregnancies results in a multiple birth in the UK3 and the ratio is much higher still in other countries. Many of the outcomes discussed in this paper are strongly influenced by the plurality of the pregnancy and birth and are mentioned in the relevant sections. It is worth noting at this stage, however, that for twin births in Western Australia in the 1980s, regardless of mode of conception, at least one of the twins of one in ten women resulted in a stillbirth, an infant death or a child with cerebral palsy4 and the figure was one in five for women with triplets. While the vast majority of multiples, particularly twins, do very well in the long term, it should not be forgotten that, compared with singletons, multiples are at an increased risk of later morbidity, including the consequences of preterm birth, and disabilities include learning disability, language delay and attention and behavioural problems.5 While not covered in this paper, which deals only with perinatal outcomes, longer-term outcomes are no less important.

The numbers of triplets in the UK rose exponentially from the mid-1980s. This reached a peak in 1998 at a rate nearly five times that before the introduction of IVF. The rate subsequently fell to a rate in 2003 of about twice the rate seen prior to the use of IVF. The decline was most likely the result of a guideline produced by the Royal College of Obstetricians and Gynaecologists and a subsequent directive from the Human Fertilisation and Embryology Authority limiting the number of embryos transferred to two/cycle in women under the age of 40 years. Multiple births, as a percentage of all live births in England and Wales, are now at the highest rate since the collection of information to distinguish multiple births from singletons began in 1938.6 This increase is thought to be largely a result of a combination of the effects of a rise in the proportion of women delivering at older ages, an increase in the use of IVF and an increase in the use of ovulation induction techniques.

Maternal medical risks associated with multiple pregnancy include an increased risk of early and late miscarriage, hypertension, pre-eclampsia, caesarean section and an increased chance of hospitalisation before the birth; all of which impact on the outcome for the babies. The immediate medical risks for the babies are being born prematurely with a low birth weight and needing neonatal intensive care.

Figure 1. mortality rates for singleton, twins and triplets, England and Wales, 2002; * rate/1000 births; ** rate/1000 live births (data source: Office for National Statistics)

3. Genetic risks

The ability of IVF, and its related procedures to overcome infertility, has led to concern that children born following these techniques will express a greater number of genetic abnormalities. It is argued that such abnormalities may be a result of transmission of genetic factors from the parents or as a result of the technique itself.

3.1 Chromosome anomalies

Somatic chromosome investigations in infertile males have shown that 13.7% of azoospermic males and 4.6% of oligozoospermic males have an abnormal karyotype. 7 In the first group, sex chromosome abnormalities predominate (mainly 47,XXY), whereas in the latter group autosome anomalies (such as Robertsonian and reciprocal translocations) are the most frequent. These findings, combined with the increased incidence of cystic fibrosis (CF) transmembrane regulator (CFTR) gene with congenital bilateral absence of vas deferens (CBAVD) (see below), have led to the introduction of genetic screening in couples undergoing ICSI. Chromosomal and CF carrier status should be checked in the male where a couple is undergoing ICSI for the indication of azoospermia or severe oligospermia, as opposed to cases of vasectomy, failed vasectomy reversal or frozen sperm post-chemotherapy.

3.2 Microdeletions and ICSI

Microdeletions of the long arm of the Y chromosome are associated with spermatogenic failure and have been used to define three azoospermia factor regions (AZFa, AZFb and AZFc) that are recurrently deleted in some infertile men. About 10-15% of men with azoospermia and about 5-10% of men with severely oligozoospermia have Yq microdeletions. ICSI with testicular sperm retrieval can be used in these circumstances, although there is the potential for transmission of genetic causes of male infertility. 8 Male infants have been born to men with an AZFc deletion following ICSI and these boys have the same microdelections as their father. 9-12

3.3 Cystic fibrosis and ICSI

Cystic fibrosis is one of the most common autosomal recessive diseases and is caused by mutations in the CFTR gene. Over 800 CFTR mutations have been identified. The most common mutation in the UK is the three base pair deletion, _F508, which accounts for 75% of carriers. The majority of adult males with CF (99%) are characterised by CBAVD. CBAVD is also found in 1-2% of men without CF who are infertile. The combination of the 5T allele in one copy of the CFTR gene with a cystic fibrosis mutation in the other copy is the most common cause of CBAVD in adult males without CF. 13 Obtaining sperm from these men for ICSI is possible through surgical retrieval but there is a resultant increase in the risk of transmitting CFTR mutations. A multiple mutations assay will detect approximately 90% of carriers of the CFTR mutation and should be offered to men with severe oligospermia.

3.4 Imprinting

Genomic imprinting is an epigenetic phenomenon by which the expression of a gene is determined by its parental origin and only one allele of the imprinted gene is expressed. Imprinting is controlled by DNA methylation in such a way that a difference in methylation between the maternal and paternal alleles correlates with different expression of the two parental alleles. Imprinted genes are the targets of molecular defects in particular rare genetic conditions including, Beckwith-Wiedemann syndrome, Angelman syndrome, Prader-Willi syndrome and Albright hereditary osteodystrophy. The reports of IVF associated with Beckwith-Wiedemann syndrome 14-16 suggest up to a six-fold increase in the risk of Beckwith-Wiedemann syndrome against a background incidence of about 1.3/100 000 newborns. However, before firm aetiological conclusions can be reached, further studies are needed to understand the relationship between imprinting, imprinting-related disorders and IVF.

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4. Maternal morbidity

As a woman gets older her chances of requiring IVF to conceive are increased. In one study, morbidity rates for both IVF and non-IVF pregnancies in primiparous women over 35 years of age were compared with rates for younger women. 17 This study demonstrated a higher rate of caesarean section delivery, preeclampsia, pregnancy-induced hypertension and gestational diabetes in the older group. All these conditions are associated with unfavourable perinatal outcomes for the neonates, including preterm delivery, low birth weight and admission for neonatal intensive care.

4.1 Recipients of donor oocytes

A specific group of women at increased risk of both maternal and perinatal morbidity are those with IVF pregnancies resulting from donor oocytes. A retrospective review of 50 consecutive donor egg IVF pregnancies compared the outcomes with those from 50 consecutive standard IVF pregnancies. 18 Key obstetric outcomes did not differ between the groups, with the exception of pregnancy-induced hypertension, which occurred in 26% of the donor recipients overall and 37% of nulliparous recipients compared with only 8% of the standard IVF group regardless of parity. Having adjusted for maternal age and multiple pregnancy, nulliparous women in the donor egg group were 7.1 times (95% CI 1.4-36.7) more likely to develop pregnancy-induced hypertension than the women in the standard IVF group.

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5. Low birth weight

Low birth weight and very low birth weight are defined as a birth weigh of less than 2500 g and less than 1500 g, respectively. The risks of low and very low birth weight following IVF were examined in two meta-analyses 19,20 that produced highly consistent results. The risk of low birth weight for IVF singletons, having controlled for a range of confounders including maternal age, was estimated at between 1.7 (95% CI 1.50-1.92) 19 and 1.8 times (95%CI 1.40-2.22) 20 higher than that of naturally conceived singletons. The risk of being a very low birth weight singleton was estimated at between 2.7 20 (95%CI 2.31-3.14) and 3.0 times (95%CI 2.07-4.36) 19 higher. While much of this increased risk may be attributed to the increased risk of prematurity associated with IVF, it is notable that there is an excess risk of being small for gestational age following IVF (see below).

Schieve et al. 21 demonstrated that for singletons, the risk of low birth weight was strongly influenced by the original number of fetal hearts evident on early ultrasound, although an excess risk remained following IVF even for singletons when only a single heart was seen originally. The proportion of low birth weight singletons ranged from 12.6% with a single early fetal heart to 50% when four fetal hearts were present originally; spontaneous versus iatrogenic reduction could not be determined. In solely spontaneously reduced IVF pregnancies, Dickey et al. 22 and Pinborg et al. 23 found consistent results, with an average reduction of 160 g and 178 g, respectively, in birth weight between singletons resulting from two original gestational sacs compared with one. Although birth weight outcomes have generally not been reported from trials of elective single embryo transfer, a lower rate of singleton low birth weight may be yet a further advantage resulting from elective single embryo transfer, a prediction confirmed in 2006 by findings from De Neubourg et al. 24

In contrast, the results for twins provide little evidence of an increased risk of low birth weight or very low birth weight following IVF. 19 Interestingly, however, the relationship between low birth weight and the original number of fetal hearts at early ultrasound remains evident, although not as extreme as for singletons. 21 The proportion of low birth weight in twins with only two fetal hearts present in early pregnancy was 53% compared with 90% when six or more fetal hearts were present originally. A similar result was not found in the smaller study of spontaneous reductions. 22

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6. Preterm birth

Subfecundity and its treatment as a whole appear to belong to the group of factors that influence both fetal weight and length of gestation. Having controlled for confounders, there is an estimated two-fold increased risk of birth before term (less than 37 weeks) for IVF singletons compared with naturally conceived singletons (RR 2.04, 95% CI 1.80-2.32; 19 OR 1.95, 95% CI 1.73-2.20 20 ). The corresponding risk for very preterm birth (less than 32 weeks) is over three-fold (RR 3.27, 95% CI 2.03-5.28). 19 As with birth weight, gestational duration appears to be influenced by the original number of fetal hearts.

Dickey et al. 22 found that singletons with only one original fetal heart present had a mean gestational age of 39.3 weeks compared with 37.9 weeks when three fetal hearts were originally present but spontaneously reduced to one. Similarly, Pinborg et al. 23 identified a mean gestational age of 38.9 weeks in singletons surviving from an original twin gestation compared with 39.5 weeks in singletons conceived as such. Again, this suggests additional benefits of elective single embryo transfer for the resulting singleton pregnancies.

As with low birth weight, the findings in relation to preterm birth for twins contrast with the findings for singletons. Twins born following IVF do not appear to be at an increased risk of preterm delivery compared with spontaneous conceptions nor very preterm delivery. 19 Again, there is some evidence of a reduction in the mean gestational of twins resulting from two original gestational sacs (36.3 weeks) compared with three originally and spontaneously reduced to two (35.7 weeks) and four originally (34.7 weeks). 22

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7. Small for gestational age

Although lacking a consistently used definition of small for gestational age (SGA), the cumulated evidence indicates there is a 40-60% excess risk of SGA in IVF singletons compared with spontaneous singletons (RR 1.40, 95% CI 1.15-1.71;19 OR 1.60, 95% CI 1.25-2.04). 20 The evidence relating to twins is less clear, with estimates ranging from no increase in the risk of SGA for IVF twins (RR 0.93, 95% CI 0.73-1.18) 19 to a nearly 30% increase (OR 1.27, 95% CI 0.97-1.65). 20

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8. Perinatal mortality

Some caution must be used in the interpretation of the pooled findings relating to perinatal mortality because of a particular lack of consistency in results across the studies pooled and the influence of one particularly large study. 19 Accepting this, the overall pooled result suggests that there is almost a 70% (RR 1.68, 95% CI 1.11-2.55) 19 increase in the risk of perinatal death for IVF singletons compared with spontaneous conceptions. The results for twins are similarly inconsistent. The combined results do suggest, however, that having adjusted for confounders, there is a decrease in the risk of perinatal death in IVF twins of between 16% (RR 0.84, 95% CI 0.53-1.32) and 42% (RR 0.58; 95%CI 0.44 to 0.77). 19 The findings from two studies of perinatal mortality demonstrated more than a three-fold increased risk of perinatal death in singletons who conceived spontaneously following a prolonged time to conception compared with singletons spontaneously conceived without a prolonged time to conception (OR 3.3, 95% CI 1.6-6.8; 25 OR 3.38, 95% CI 1.51-7.54). 26

9. Congenital anomalies

Despite methodological differences, three meta-analyses from 2004-05 provide us with remarkably similar estimates of the overall increased risk of congenital anomalies associated with IVF. Rimm et al. 27 (OR 1.29, 95% CI 1.01-1.67), Hansen et al. 28 (OR 1.29, 95% CI 1.21-1.37) and McDonald et al. 29 (OR 1.41, 1.06-1.88) estimated from pooled data controlled for confounders, that there was approximately a 30% increased risk of congenital anomalies in infants born following IVF compared with spontaneous conception. Data from a systematic review, however, suggests that the increased risk may be as high as 40% 28 (OR 1.40, 95% CI 1.28-1.53). The excess risk is not due solely to the effects of the increased risk of congenital anomalies associated with multiple birth. When only singleton pregnancies were considered the excess risk remained (OR 1.31, 95% CI 1.17-1.46). 28 It is not clear from the available data which particular anomalies or groups of anomalies are present in excess following IVF. This is not surprising, since most of the studies conducted to date have been of insufficient size to properly investigate the incidence of congenital anomalies overall, let alone single diagnostic groups. 30 Large population-based studies are now required to allow the investigation of the incidence of specific anomalies, the role of different underlying causes of the infertility and specific aspects of treatment.

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10. Specific IVF and related procedures

10.1 Preimplantation genetic diagnosis

Preimplantation genetic diagnosis is a technique which involves the genetic testing of embryos created in vitro for deleterious, inherited genetic conditions known to be present in the family of those seeking treatment and from which the embryos are at risk. The purpose of preimplantation genetic diagnosis is to provide information that allows unaffected embryos to be selected for transfer. The technique involves the removal of one or more blastomeres, the testing of the blastomeres for the specific genetic condition(s) and the transfer of unaffected embryos. Since its introduction in 1990, preimplantation genetic diagnosis has been applied to an increasing number of single gene disorders, chromosomal rearrangements and more recent indications such as aneuploidy screening and HLA matching. Over 1000 children have been born worldwide following preimplantation genetic diagnosis. Current opinion is that there is no increase in the risk of adverse perinatal outcomes following the procedure but continuing surveillance is required to confirm this. 31,32

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10.2 Blastocyst culture

The extended culture of embryos in vitro from the traditional day 2 transfer date to day 5 (blastocyst stage) has been advocated as a means of improving embryo selection and thus pregnancy rates. The embryo is sequentially cultured in different media to facilitate in vitro development. Studies in mice and calves have raised some concerns about blastocyst culture, since male embryos reach the blastocyst stage faster than female embryos, resulting in a higher proportion of male offspring. However, in humans, these findings have not been reproduced and there is no evidence to date to suggest an adverse effect on perinatal health following blastocyst transfer having adjusted for multiple pregnancy. 33 These studies have been relatively small (largest 500 babies) and retrospective, with no follow-up beyond day 5 after birth, so no definitive conclusion can yet be reached. There has, however, been a reported increase in monozygous twinning rate following blastocyst transfer, 34 with the associated poorer perinatal outcomes of monozygotic twins. A recent Cochrane review concluded that embryo transfer on day 2 or 3 and day 5 or 6 appears to be equally effective in terms of pregnancy rate and livebirth rate/cycle started. 35 A 2006 randomised controlled trial has, however, suggested that there may be a sub-population of women under the age of 36 years where day 5 transfer will give a significantly higher pregnancy and livebirth rate than day 2 transfer. 36

10.3 Assisted hatching

Assisted hatching has been developed as a method to disrupt the zona pellucida, which has been suggested as facilitating and enhancing implantation and pregnancy rates, especially in older women. A systematic review of 23 randomised controlled trials including 2572 women concluded that the trials to date provided insufficient data to investigate the impact of assisted hatching on neonatal outcomes, including monozygotic twinning, embryo damage, congenital and chromosomal abnormalities. 37 The individual studies have suggested no increase in the rate of major congenital malformations, although monoamniotic multiple gestation may be increased in zona-manipulated cycles. The current UK recommendation is that assisted hatching is not performed, as it has not been shown to improve pregnancy rates. 38

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11. Conclusions

It is as yet unclear what are all the factors that place IVF pregnancies at an increased risk of perinatal mortality and other adverse perinatal outcomes. Factors may be related to aspects of the treatment or the underlying features that the couple brings to the pregnancy or a mixture of both, with evidence pointing to both effects. 21,25,39 Further research is needed to untangle the complex relationship between the risks associated with aspects of the treatment from the risks brought to the conception and pregnancy by the couple being treated, to describe in detail the perinatal characteristics of infants born following elective single embryo transfer and to understand the relative differences in outcome of IVF twins compared with spontaneous twins versus the situation for singletons. In the meantime, we must ensure that, while IVF is now an established routine medical procedure, prospective recipients do not equate routine with being completely safe and the outcomes being completely risk-free for the infants. 40

Summary of key points

  1. About 25% of all IVF maternities in the UK result in multiple births: multiple conception has the single most significant effect on perinatal outcome following IVF.
  2. IVF pregnancies in general have higher rates of most adverse perinatal outcomes compared with spontaneously conceived pregnancies. Some but not all of the excess risk is related to multiple pregnancies.
  3. There are insufficient data available to state reliably the safety or otherwise of specific processes associated with IVF, including preimplantation genetic diagnosis, blastocyst culture and assisted hatching.
  4. Characteristics of the population who require IVF, such as being older or having genetic perturbations, may contribute to an increase in perinatal risk for any resulting pregnancy.

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References

  1. Davidson L, Quigley M. Millennium Cohort Study. Women-s experience of successful infertility treatment: results from the MCS fertility survey . London: Centre for Longitudinal Studies; 2006 [www.cls.ioe.ac.uk].
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  3. Human Fertilisation and Embryology Authority. The HFEA Guide to Infertility and Directory of Clinics, 2005/06 . London: HFEA; 2005.
  4. Petterson B, Nelson KB, Watson L, Stanley FJ. Twins, triplets and cerebral palsy in births in Western Australia in the 1980s. Br Med J 1993;307:1239-43.
  5. Allen MC. Factors affecting developmental outcome. In: Keith LG, Papiernick E, Keith DM, Luke B, editors. Multiple Pregnancy, Epidemiology, Gestation and Perinatal Outcome . New York: Parthenon Publishing Group; 1995.
  6. Kurinczuk JJ. Epidemiology of multiple pregnancy: changing effects of assisted conception. In: Kilby M, Baker P, Critchley H, Field D, editors. Multiple Pregnancy . London: RCOG Press; 2006.
  7. Van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, et al. Cytogenetics of infertile men. Hum Reprod 1996;11(Suppl 4):1-24; discussion 25-6.
  8. Krausz C, Forti G, McElreavey K. The Y chromosome and male fertility and infertility. Int J Andro l 2003;26:70-5.
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  10. Kamischke A, Gromoll J, Simoni M, Behre HM, Nieschlag E. Transmission of a Y chromosome delection involving the deletion in azoospermia (DAZ) and chromodomain (CDYI) genes from father to son through intracytoplasmic sperm injection. Hum Reprod 1999;14:2320-2.
  11. Page DC, Silber S, Brown LG. Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility. Hum Reprod 1999;14:1722-6.
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  13. Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995;332:1475-80.
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  15. Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet 2003;361:1975-7.
  16. Sutcliffe AG, Peters CJ, Bowdin S, Temple K, Reardon W, et al. Assisted reproductive therapies and imprinting disorders - a preliminary British survey. Hum Reprod 2006; 21:1009-11.
  17. Healy D. Are Primiparous Women of Advanced Maternal Age at Increased Risk perinatal outcome? Monash: Centre of Clinical effectiveness, Monash University; 1998.
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  27. Rimm AA, Katayama AC, Diaz M, Katayama KP. A meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children. J Assist Reprod Genet. 2004;21:437-43.
  28. Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects: a systematic review. Hum Reprod 2005;20:328-38.
  29. McDonald SD, Murphy K, Beyene J, Ohlsson A. Perinatal outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Obstet Gynaecol Can 2005;27:449-59.
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  34. Milki AA, Jun SH, Hinckley MD, Behr B, Giudice LC, Westphal LM. Incidence of monozygotic twinning with blastocyst transfer compared to cleavage-stage transfer. Fertil Steril 2003;79:503-6.
  35. Blake D, Proctor M, Johnson N, Olive D. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochrane Database Syst Rev 2002;(2):CD002118 [update in Cochrane Database Syst Rev 2005;(4):CD002118]
  36. Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuty L, Van Steireghem A, Devroey P. In Vitro fertilisation with single balstocyst-stage versus single cleavage-stage embryos. N Engl J Med 2006;354:1190-3.
  37. Edi-Osagie EC, Hooper L, McGinlay P, Seif MW. Effect(s) of assisted hatching on assisted conception (IVF & ICSI). Cochrane Database Syst Rev 2003;(4):CD001894.
  38. National Collaborating Centre for Women-s and Children-s Health. Fertility: Assessment and Treatment for People with Fertility Problems. London: RCOG Press; 2004.
  39. Williams MA, Goldman MB, Mittendorf R, Monson RR. Subfertility and the risk of low birth weight. Fertil Steril 1991;56:668-71.
  40. Kurinczuk JJ. Safety issues in assisted reproductive technology. From theory to reality: just what are the data telling us about ICSI offspring health and future fertility and should we be concerned? Hum Reprod 2003;18:925-31.

 

This opinion paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Dr JE McVeigh MRCOG, Oxford, and Dr JJ Kurinczuk MD MSc FFPH, Oxford,
and peer reviewed by:
Dr AV Akande MRCOG, Bristol; Professor S Bhattacharya MRCOG, Aberdeen; Dr M Bonduelle, Centre for Medical Genetics, Brussels; Professor KL Costeloe, Professor of Paediatrics, Neonatal Unit, Homerton University Hospital, London.

The final version is the responsibility of the Scientific Advisory Committee of the RCOG.

 

Date published: 01/02/2007

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