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Assisted reproduction: a paediatrician’s guide
Current Paediatrics (2000) 10, 301–305 © 2000 Harcourt Publishers Ltd doi:10.1054/ cupe.2000.0130, available online at http://www.idealibrary.com on
Occasional review
Assisted reproduction: a paediatrician’s guide
S. R. Watermeyer, N. N. Amso Worldwide, a significant number of pregnancies and births are attributable to assisted reproductive techniques (ART). This has implications for the paediatricians caring for the resultant offspring. The most significant factors affecting ART pregnancies are those associated with multiple pregnancy and prematurity. There does not appear to be an increased risk of major congenital abnormality or malignancy in children born by these methods, although with intracytoplasmic sperm injection (ICSI), there is an increase in the risk of hypospadias. Since ICSI is a new procedure, there are possible unforeseen complications with children resulting from the technique, of which the risk of infertility is one. © 2000 Harcourt Publishers Ltd
Keywords: assisted reproduction treatment; IVF; multiple pregnancy; perinatal mortality; cancer; congenital anomalies
PRACTICE POINTS
• • • • • •
•
Assisted reproductive techniques (ART) are associated with prematurity and multiple pregnancy The incidence of triplets or higher order multiple births is decreased when two as opposed to three embryos are replaced in an in-vitro fertilization (IVF) cycle The British Fertility Society advocates the transfer of a maximum of two embryos as a measure of good practice There is no increased risk of major congenital abnormalities secondary to ART Intracytoplasmic sperm injection (ICSI) is associated with an increased risk of hypospadias There is no increased risk of the development of malignancies secondary to ART
•
•
Women with a history of infertility treated or untreated may have a significantly increased risk of perinatal death Singleton IVF pregnancies have a significantly increased incidence of intrauterine growth restriction, placenta praevia and preterm delivery in comparison with spontaneously conceived pregnancies Singleton and twin IVF pregnancies are more likely to be delivered by caesarean section.
INTRODUCTION Following the first successful IVF treatment carried out in Oldham, UK, fertility clinics were set up and have flourished. An impressive array of ART are now widely available. These include ovulation induction, artificial insemination with husband’s sperm or donor (DI), gamete intrafallopian transfer (GIFT), IVF and ICSI. These techniques can be undertaken with donor oocytes or donor sperm. Surrogacy or the use of another woman’s uterus is also now accepted practice in the UK and worldwide. With more and more births directly attributable to ART, it is becoming
Sean R. Watermeyer, Nazar N. Amso, Department of Obstetrics and Gynaecology, University Hospital of Wales, Cardiff CF14 4XN, UK. Correspondence to SRW.
301
Current Paediatrics
ASSISTED REPRODUCTION TREATMENTS Simple treatments such as ovulation induction with clomiphene citrate have a low success rate, but equally are associated with low multiple pregnancy rates of approximately 6–7%. The use of exogenous gonadotrophins such as human menopausal gonadotrophin (hMG), pure follicle stimulating hormone or recombinant follicle stimulating hormone (r-FSH) for stimulation of ovulation is associated with higher pregnancy and live birth rates, but at the cost of high multiple pregnancy rates of 20–38% of pregnancies. Whether intrauterine insemination is carried out or not, the incidence of multiple pregnancy is dependent on the total number of developing follicles and the number of mature follicles at the time of human chorionic gonadotrophin administration. More complex treatments such as IVF, ICSI and egg or embryo donation involve further steps additional to ovulation induction. These include more complex monitoring with ultrasound and hormone assays, oocyte recovery under general anaesthesia or sedation, elaborate laboratory procedures for in-vitro insemination or microinjection techniques, and replacement of embryos into the uterine cavity or the fallopian tube. Gamete intrafallopian transfer treatment, where eggs and sperm are placed into the fallopian tube, is less commonly practised at present due to the additional laparoscopy procedure and the lack of evidence of any higher pregnancy rates in comparison with IVF.
FACTORS AFFECTING TREATMENT OUTCOME The likelihood of pregnancy and live birth following ART is dependent on a number of clinical factors that significantly affect the outcome. It is also clear from the Human Fertilisation and Embryology Authority (HFEA) annual reports that the outcome of treatment varies between small and large centres. Woman’s age at the time of treatment is an important prognostic factor as the number of oocytes
25 Live birth rate (%)
increasingly important for the paediatrician to be aware of the potential perinatal hazards associated with such treatments. This paper will outline the treatments available and the factors that influence the outcome of treatment, and will attempt to investigate any differences between the outcome of normally conceived pregnancies and those achieved with the help of ART. More specifically, we will look at whether ART affects the pregnancy itself and mode of delivery, with any associated consequences for the neonate. Peri-and neonatal complications, as well as fears over a possible increase in anatomical and/or chromosomal anomalies in babies born to mothers who have had ART, will be discussed.
20 15 10 5 0 1991 / 92
1992/ 93
1993 / 94
1994/ 95
1995/ 96
1996 / 97
1997/ 98
Treatment cycles Fig. 1 Live birth rate per treatment cycle 1991–1998 (HFEA 1999), –––– ◆ , in-vitro fertilization; –––– ■ , micromanipulation; –––– ▲ , artificial insemination with donor sperm.
Live birth rate (%)
302
30 25 20 15 10 5 0 < 27
27 – 28 29 – 30 31 – 32 33 – 34 35 –36 37 – 38 39 – 40 41 – 42 43 – 44
> 45
Age of women (years) Fig. 2 Live birth rate by age of women (HFEA 1999), –––– ◆ , in-vitro fertilization; ------■ , micromanipulation (own eggs).
retrieved, and consequently the number of embryos available for transfer, decline with age. Although live birth rates per treatment cycle following IVF, ICSI, and DI have increased consistently over the past decade (Fig. 1), they decline with advancing age when women’s own eggs are used (Fig. 2). It would appear that the cut-off point of effectiveness for IVF is the age of 36–37 years, with marked decline in women over the age of 38. However, older women with good ovarian response, producing three or more embryos suitable for transfer after IVF or ICSI, have pregnancy rates similar to younger women, although the age-related risk of trisomy is increased in resultant offspring. The cause of infertility has little impact on the IVF clinical pregnancy and live birth rates, although lowest rates were reported for multiple infertility factors and male infertility when conventional IVF treatment was offered. The HFEA report of 19991 showed similar results for tubal disease, endometriosis and unexplained infertility. With the introduction of ICSI, higher fertilization rates have been achieved and the pregnancy and live birth rates for male infertility have considerably improved in the past few years (Fig. 1). The duration of infertility is one of the most significant variables that affect ART outcome. Analysis of the HFEA database between 1991 and 1994 showed that, even with adjustment for age, there was a significant decrease in the live birth rate with increasing duration of infertility. The number of embryos transferred correlates with the pregnancy and live birth rates as well as the multiple pregnancy rates. Concern about the latter resulted
Assisted reproduction in the HFEA restricting the number of embryos transferred to three. However, multiple pregnancy rates remain high with all the accompanying complications. The most recent HFEA report1 showed that when four or more fertilized eggs were available, the transfer of three embryos did not result in improved pregnancy rates compared with the elective transfer of two embryos. However, the incidence of triplets or higher order multiple births decreased considerably when two embryos were replaced. The British Fertility Society advocates the transfer of a maximum of two embryos as a measure of good practice. Other factors also have considerable impact on the cumulative pregnancy and live birth rates. These include the type of stimulation protocol used, the total number of oocytes retrieved and fertilized, the stage at which embryos are transferred, the number of surplus embryos available for cryopreservation, luteal phase support, and the number of attempts of ART procedures that a couple undergo. Detailed discussion is beyond the scope of this paper and the reader should consult specialist textbooks for further information. ANTENATAL COMPLICATIONS OF ART A large series2 reported no increase in the spontaneous miscarriage rate following IVF in comparison with natural conceptions. However, a higher incidence of multiple pregnancy, vaginal bleeding and hypertension requiring hospitalization were reported.3 Even among IVF singleton pregnancies, there was a significantly increased incidence of intrauterine growth restriction, placenta praevia and preterm delivery. These obstetric risks may reflect the women’s history of infertility and a relatively high incidence of a poor obstetric history. In-vitro fertilization mothers may have a higher incidence of pregnancy-induced hypertension, premature labour, labour induction and preterm delivery4, and multiple pregnancies have a higher prevalence of pre-eclampsia. Comparison of singleton IVF pregnancies with matched controls showed a longer first stage of labour, greater intrapartum blood loss and a trend towards a higher caesarean delivery than controls.5 Twin IVF pregnancies were comparable to naturally conceived twins in their mean gestational age at delivery, rates of induction of labour and mode of delivery. Women who conceived following oocyte donation, especially with a history of ovarian failure, should be considered as ‘high risk’. Analysis of 232 ovum donation pregnancies reported a higher risk of pregnancyinduced hypertension and postpartum haemorrhage, as well as an increased incidence of ‘small for gestational age’ infants and an operative delivery rate of 85%.6 Retrospective comparison of ICSI pregnancies with matched IVF controls showed similar early pregnancy fetal loss and multiple pregnancy rates.
303
More recently, pregnancies resulting from the transfer of fresh or frozen conventional IVF or ICSI were compared.7 The frozen ICSI group showed a significantly higher miscarriage rate than the frozen conventional IVF patients. Other complications relating to multiple pregnancy and prematurity will be discussed in the next section.
PERINATAL AND PAEDIATRIC OUTCOME OF ART Multiple pregnancy and prematurity An increase in twinning and triplet rates in developed countries such as England and Wales, Germany, The Netherlands, Switzerland and others has been attributed to the higher proportion of mothers treated with ovulation-inducing hormones, and partially attributed to IVF. It is widely accepted that multiple pregnancies account for a disproportionately large share of adverse pregnancy outcomes8, including increased incidence of (very) low birth weight, perinatal and neonatal mortality, as well as infant death. The increased incidence of death and morbidity in twin as compared with singleton pregnancies has been attributed mainly to prematurity9 and to adverse outcomes associated with premature delivery such as hyaline membrane disease, hypocalcaemia, hypoglycaemia, hyperbilirubinaemia, small for dates, and low apgar scores. In one recent study10, the contribution of IVF on changes in the incidence of low birth weight, preterm delivery, and multiple birth over a 3-year period was substantial. The increased incidence of preterm delivery and low birth weight was partly related to multiple births, though an increase in preterm deliveries has also been seen in IVF singleton pregnancies.11 As indicated earlier, there is increasing evidence that transferring two embryos instead of three does not compromise of the chance of pregnancy, and this appears to reduce the risk of triplets. Experience worldwide appears to be similar. Other studies report a multiple pregnancy rate of 14.3% for double embryo transfers and 32.4% for triple embryo transfers, with no significant difference in the pregnancy rate if at least one good quality embryo was available for transfer. It may be that the outcome of IVF-conceived twin pregnancies is comparable with that of normally conceived twins in terms of duration of gestation, birth weight, perinatal death, perinatal morbidity and incidence of congenital malformations.11 However, earlier evidence suggests that ART twin pregnancies have a higher incidence of preterm deliveries and need more neonatal intensive care when compared with matched control twin pregnancies.12 Interestingly, for both singleton and twin pregnancies obtained with IVF, the incidence of caesarean section is increased.11 This may in part be a reflection of the generally held medical perception of ART pregnancies being ‘precious’ and
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Current Paediatrics
hence a lower threshold for intervention by obstetricians, but may also indicate a higher complication rate necessitating operative delivery. Perinatal mortality/morbidity Early follow-up studies suggest that the still birth and perinatal mortality rates following IVF are comparable with national maternal age-standardized rates.3 In-vitro fertilization conceived twins have comparable perinatal mortality rates to their spontaneously conceived controls.11 Singleton IVF pregnancies are reported to have significantly worse perinatal outcome in comparison to spontaneously conceived pregnancies, mainly because of the increased rate of preterm birth.11 Other workers13 have found a doubling of the premature birth rate in singleton post infertility pregnancies when compared with normal controls, with an increased mortality rate. In-vitro fertilization infants may have a lower mean birth weight, more frequent occurrence of low birth weight, and a shorter gestation. Additionally, these infants may have longer hospitalizations, more days of oxygen therapy and continuous positive airway pressure, as well as increased prevalence of respiratory distress syndrome, patent ductus arteriosus, and sepsis.4 The same study concluded that couples who underwent IVF appear to be at increased risk of having low birth weight and preterm infants, but multiple gestations accounted for most of the neonatal morbidities. Births following ICSI treatment or resulting from the transfer of cryopreserved embryos did not differ from their respective controls.14,15 It is logical to assume that women with infertility problems are likely to have an increased incidence of pelvic or, for that matter, systemic pathology to account for their subfertile/infertile status. It therefore follows that such women having achieved a pregnancy would be susceptible to an increase in complication rates. Indeed, it has been reported that women with a past medical history of infertility, whether treated or untreated, may have a significantly increased risk of perinatal death.16 The same study showed that women with untreated infertility are at increased risk of perinatal death and any association with multiple births did not explain this finding. The same was true of women with treated infertility; the risks of associated multiple births explained some but not all of this excess. The authors advocate that at antenatal booking, a history of infertility, irrespective of treatment, should be sought due to the significantly increased risk of perinatal death. INCIDENCE OF CANCER It is important for potential parents utilizing ART, especially IVF and ICSI, to be counselled on the likely outcome of their unborn children’s health, especially any life-threatening illnesses such as cancer. There have been case reports17 of paediatric tumours in children conceived by IVF. For example, two children
12 and 18 months of age developed hepatoblastoma and clear cell carcinoma of the kidney. A possible association between IVF and paediatric malignancies has been suggested. However, ART are not generally considered to be associated with an increased rate of paediatric malignancies. Recent studies18 did not find any significantly increased incidence of cancer in children conceived using IVF and related procedures in comparison with the general population. Larger studies are needed to reach definite conclusions. IN-VITRO FERTILIZATION/ ICSI AND CONGENITAL ABNORMALITIES No increase in the malformation rate has been noted in children born following conventional IVF.3 Intracytoplasmic sperm injection, which was first successful in 1992, enabled men who had previously been diagnosed with severe male factor infertility, the chance to have their own genetic children and pass their genes on to their own progeny; an event that may not have been possible just a few years ago. This raises certain questions about the genetic constitution of any resulting pregnancies. Following ICSI, the quality of the sperm used may adversely affect the chromosome constitution of the resulting embryo.19 This particular case report utilized fluorescence in-situ hybridization (FISH) to determine any chromosomal abnormalities in embryos prior to implantation. An infertile couple with severe male infertility and endometriosis underwent two ICSI cycles with husband’s sperm and one IVF cycle with donor sperm. Pre-implantation genetic diagnosis with FISH showed that all the embryos derived from the cycle in which donor sperm was used were chromosomally normal, whereas 82% of embryos derived from cycles in which the husband’s sperm was used were chromosomally abnormal. It was concluded that paternal factors, thought to be derived from the paternal centrosome, could have contributed to the numerical chromosomal abnormalities and may, in turn, have predisposed to implantation failure. It is possible that they would be manifested as congenital abnormalities that present to the paediatrician. The cycle in which donor sperm was used resulted in an ongoing pregnancy. However, short- and long-term follow-up data on children born by ICSI have thus far been encouraging. One recent study14 showed no difference in the incidence of multiple pregnancies and perinatal outcome between standard IVF and ICSI. Furthermore, no major malformations were noted. In another retrospective follow-up study20, 132 children born after IVF and 120 after ICSI were analysed. No differences were found between the two groups for early embryonic development and obstetric outcome. The congenital malformation rate was 3% after IVF and 1.7% after ICSI. In both groups, the rate of women undergoing prenatal chromosomal diagnosis was low (30%). A 7-year prospective follow-up study21 of 1987 -
Assisted reproduction children born after ICSI compiled data on karyotypes, congenital malformations, growth parameters and developmental milestones. Prenatal diagnosis, as well as physical examination of the children at 2 months, 1 year and 2 years, was performed. The subgroups examined were children born after ICSI with ejaculated, epididymal and testicular spermatozoa. The Belgian group did not find any specifically higher incidence of malformations in any subgroup. One condition that does appear to be directly associated with ICSI is hypospadias. In over 1000 babies born after ICSI, seven cases of hypospadias were identified with an expectation in the general population of around two.22 Hypospadias appears to be associated with paternal subfertility so a link with ICSI is possible. The same study showed an increased risk of abnormalities in babies born after ICSI compared with babies born without the use of fertility treatment. However, this was mainly due to conditions associated with multiple or premature births, rather than the ICSI treatment itself. Couples requiring ICSI appear to have an increased incidence of chromosomal disorders and this appears to manifest itself as a low implantation rate.23 The risk of transmitting chromosomal aberrations can be minimized by karyotyping potential parents, pre-implantation genetic diagnosis and prenatal fetal karyotyping. There is also the long-term risk of transmitting fertility problems to the offspring. So far, about 20 000 babies have been born worldwide through ICSI in the last decade, and the vast majority of these are healthy normal children. Since ICSI is still a relatively new procedure, further follow-up studies are required. Potential parents may be reassured that, generally, there appears to be no higher incidence of major congenital malformations in children born after this procedure. CONCLUSION Overall, the paediatrician needs to be aware that probably the two most significant factors affecting assisted reproduction pregnancies are those associated with multiple pregnancy and prematurity. There does not appear to be any increased risk of major congenital abnormalities secondary to assisted reproduction procedures themselves, and the risk to children of developing malignancies does not appear to be greater than that of the general population. Women with a past medical history of infertility appear to have worse perinatal outcomes, possibly enhanced if they are oocyte recipients. Finally, ICSI does not appear to increase the incidence of major congenital malformations, although there is an increase in the incidence of hypospadias. Since it is still a relatively new procedure, potential parents should be made aware of the possible unforeseen complications and the risk of infertility of any resulting children.
305
REFERENCES 1. Human Fertilisation and Embryology Authority. Eighth Annual Report & Accounts. London: The Stationary Office, 1999. 2. Alsalili, Yuzpe A, Tummon I et al. Cumulative pregnancy rates and pregnancy outcome after in-vitro fertilization. Hum Reprod 1995; 10: 470–474. 3. Tan S L, Doyle P, Campbell S et al. Obstetric outcome of in vitro fertilisation pregnancies compared with normally conceived pregnancies. Am J Obstet Gynecol 1992; 167: 778–784. 4. Tallo C P, Vohr B, Oh W, Rubin L P, Seifer D B, Haning R V Jr. Maternal and neonatal morbidity associated with in vitro fertilization. J Pediatr 1995; 127: 794–800. 5. Howe RS, Sayegh RA, Durinzi KL, Tureck RW. Perinatal outcome of singleton pregnancies conceived by in vitro fertilization: a controlled study. J Perinatol 1990; 10: 261–266. 6. Abdalla H I, Billet A, Kan A K et al. Obstetric outcome in 232 ovum donation pregnancies. Br J Obstet Gynaecol 1998; 105: 332–337. 7. Aytoz A, Van den Abbeel E, Bonduelle M et al. Obstetric outcome of pregnancies after transfer of cryopreserved and fresh embryos obtained. Hum Reprod 1999; 14: 2619–2624. 8. Powers W F, Kiely J L. The risks confronting twins: a national perspective. Am J Obstet Gynecol 1994; 170: 456–461. 9. Ho S K, Wu P Y. Perinatal factors and neonatal morbidity in twin pregnancy. Am J Obstet Gynecol 1975; 122: 979–987. 10. Tough S C, Greene C A, Svenson L W, Belik J. Effects of in vitro fertilisation on low birth weight, preterm delivery, and multiple birth. J Pediatr 2000; 136: 618–622. 11. Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal outcome of pregnancies after assisted reproduction: a case controlled study. Am J Obstet Gynecol 1999; 181: 688–695. 12. Dhont M, De Neubourg F, Van der Elst J, De Sutter P. Perinatal outcome of pregnancies after assisted reproduction: a case-control study. J Assist Reprod Genet 1997; 14: 575–580. 13. Ishii S, Tanaka K, Okai T et al. Perinatal outcome of pregnancies following therapy of infertility. Nippon Sanka Fujinka Gakkai Zasshi 1994; 46: 1305–1310. 14. Bider D, Livshitz A, Tur Kaspa I, Shulman A, Levron J, Dor J. Incidence and perinatal outcome of multiple pregnancies after intracytoplasmic sperm injection compared to standard in vitro fertilization. J Assist Reprod Genet 1999; 16: 221–226. 15. Wada I, Macnamee MC, Wick K, Bradfield JM, Brinsden PR. Birth characteristics and perinatal outcome of babies conceived from cryopreserved embryos. Hum Reprod 1994; 9: 543–546. 16. Draper E S, Kurinczuk J J, Abrams K R, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 1999; 353: 1746–1749. 17. Toren A, Sharon N, Mandel M et al. Two embryonal cancers after in vitro fertilisation. Cancer 1995; 76: 2372–2374. 18. Bruinsma F, Venn A, Lancaster P, Speirs A, Healy D. Incidence of cancer in children born after in-vitro fertilization. Hum Reprod 2000; 15: 604–607. 19. Obasaju M, Kadam A, Sultan K, Fateh M, Munne S. Sperm quality may adversely affect the chromosome constitution of embryos that result from intracytoplasmic sperm injection. Fertil Steril 1999; 72: 1113–1115. 20. Van Golde R, Boada M, Veiga A, Evers J, Geraedts J, Barri P. A retrospective follow-up study on intracytoplasmic sperm injection. J Assist Reprod Genet 1999; 16: 227–232. 21. Bonduelle M, Camus M, De Vos A et al. Seven years of intracytoplasmic sperm injection and follow up of 1987 subsequent children. Hum Reprod 1999; 14 (Suppl. 1): 243–264. 22. Wennerholm U B, Bergh C, Hamberger et al. Incidence of congenital malformations in children born after ICSI. Hum Reprod 2000; 15: 944–948. 23. Scholtes M C, Behrend C, Dietzel-Dahmen J et al. Chromosome aberrations in couples undergoing intracytoplasmic sperm injection: influence on the implantation and ongoing pregnancy rates. Fertil Steril 1998; 70: 933–937.
Occasional review
Assisted reproduction: a paediatrician’s guide
S. R. Watermeyer, N. N. Amso Worldwide, a significant number of pregnancies and births are attributable to assisted reproductive techniques (ART). This has implications for the paediatricians caring for the resultant offspring. The most significant factors affecting ART pregnancies are those associated with multiple pregnancy and prematurity. There does not appear to be an increased risk of major congenital abnormality or malignancy in children born by these methods, although with intracytoplasmic sperm injection (ICSI), there is an increase in the risk of hypospadias. Since ICSI is a new procedure, there are possible unforeseen complications with children resulting from the technique, of which the risk of infertility is one. © 2000 Harcourt Publishers Ltd
Keywords: assisted reproduction treatment; IVF; multiple pregnancy; perinatal mortality; cancer; congenital anomalies
PRACTICE POINTS
• • • • • •
•
Assisted reproductive techniques (ART) are associated with prematurity and multiple pregnancy The incidence of triplets or higher order multiple births is decreased when two as opposed to three embryos are replaced in an in-vitro fertilization (IVF) cycle The British Fertility Society advocates the transfer of a maximum of two embryos as a measure of good practice There is no increased risk of major congenital abnormalities secondary to ART Intracytoplasmic sperm injection (ICSI) is associated with an increased risk of hypospadias There is no increased risk of the development of malignancies secondary to ART
•
•
Women with a history of infertility treated or untreated may have a significantly increased risk of perinatal death Singleton IVF pregnancies have a significantly increased incidence of intrauterine growth restriction, placenta praevia and preterm delivery in comparison with spontaneously conceived pregnancies Singleton and twin IVF pregnancies are more likely to be delivered by caesarean section.
INTRODUCTION Following the first successful IVF treatment carried out in Oldham, UK, fertility clinics were set up and have flourished. An impressive array of ART are now widely available. These include ovulation induction, artificial insemination with husband’s sperm or donor (DI), gamete intrafallopian transfer (GIFT), IVF and ICSI. These techniques can be undertaken with donor oocytes or donor sperm. Surrogacy or the use of another woman’s uterus is also now accepted practice in the UK and worldwide. With more and more births directly attributable to ART, it is becoming
Sean R. Watermeyer, Nazar N. Amso, Department of Obstetrics and Gynaecology, University Hospital of Wales, Cardiff CF14 4XN, UK. Correspondence to SRW.
301
Current Paediatrics
ASSISTED REPRODUCTION TREATMENTS Simple treatments such as ovulation induction with clomiphene citrate have a low success rate, but equally are associated with low multiple pregnancy rates of approximately 6–7%. The use of exogenous gonadotrophins such as human menopausal gonadotrophin (hMG), pure follicle stimulating hormone or recombinant follicle stimulating hormone (r-FSH) for stimulation of ovulation is associated with higher pregnancy and live birth rates, but at the cost of high multiple pregnancy rates of 20–38% of pregnancies. Whether intrauterine insemination is carried out or not, the incidence of multiple pregnancy is dependent on the total number of developing follicles and the number of mature follicles at the time of human chorionic gonadotrophin administration. More complex treatments such as IVF, ICSI and egg or embryo donation involve further steps additional to ovulation induction. These include more complex monitoring with ultrasound and hormone assays, oocyte recovery under general anaesthesia or sedation, elaborate laboratory procedures for in-vitro insemination or microinjection techniques, and replacement of embryos into the uterine cavity or the fallopian tube. Gamete intrafallopian transfer treatment, where eggs and sperm are placed into the fallopian tube, is less commonly practised at present due to the additional laparoscopy procedure and the lack of evidence of any higher pregnancy rates in comparison with IVF.
FACTORS AFFECTING TREATMENT OUTCOME The likelihood of pregnancy and live birth following ART is dependent on a number of clinical factors that significantly affect the outcome. It is also clear from the Human Fertilisation and Embryology Authority (HFEA) annual reports that the outcome of treatment varies between small and large centres. Woman’s age at the time of treatment is an important prognostic factor as the number of oocytes
25 Live birth rate (%)
increasingly important for the paediatrician to be aware of the potential perinatal hazards associated with such treatments. This paper will outline the treatments available and the factors that influence the outcome of treatment, and will attempt to investigate any differences between the outcome of normally conceived pregnancies and those achieved with the help of ART. More specifically, we will look at whether ART affects the pregnancy itself and mode of delivery, with any associated consequences for the neonate. Peri-and neonatal complications, as well as fears over a possible increase in anatomical and/or chromosomal anomalies in babies born to mothers who have had ART, will be discussed.
20 15 10 5 0 1991 / 92
1992/ 93
1993 / 94
1994/ 95
1995/ 96
1996 / 97
1997/ 98
Treatment cycles Fig. 1 Live birth rate per treatment cycle 1991–1998 (HFEA 1999), –––– ◆ , in-vitro fertilization; –––– ■ , micromanipulation; –––– ▲ , artificial insemination with donor sperm.
Live birth rate (%)
302
30 25 20 15 10 5 0 < 27
27 – 28 29 – 30 31 – 32 33 – 34 35 –36 37 – 38 39 – 40 41 – 42 43 – 44
> 45
Age of women (years) Fig. 2 Live birth rate by age of women (HFEA 1999), –––– ◆ , in-vitro fertilization; ------■ , micromanipulation (own eggs).
retrieved, and consequently the number of embryos available for transfer, decline with age. Although live birth rates per treatment cycle following IVF, ICSI, and DI have increased consistently over the past decade (Fig. 1), they decline with advancing age when women’s own eggs are used (Fig. 2). It would appear that the cut-off point of effectiveness for IVF is the age of 36–37 years, with marked decline in women over the age of 38. However, older women with good ovarian response, producing three or more embryos suitable for transfer after IVF or ICSI, have pregnancy rates similar to younger women, although the age-related risk of trisomy is increased in resultant offspring. The cause of infertility has little impact on the IVF clinical pregnancy and live birth rates, although lowest rates were reported for multiple infertility factors and male infertility when conventional IVF treatment was offered. The HFEA report of 19991 showed similar results for tubal disease, endometriosis and unexplained infertility. With the introduction of ICSI, higher fertilization rates have been achieved and the pregnancy and live birth rates for male infertility have considerably improved in the past few years (Fig. 1). The duration of infertility is one of the most significant variables that affect ART outcome. Analysis of the HFEA database between 1991 and 1994 showed that, even with adjustment for age, there was a significant decrease in the live birth rate with increasing duration of infertility. The number of embryos transferred correlates with the pregnancy and live birth rates as well as the multiple pregnancy rates. Concern about the latter resulted
Assisted reproduction in the HFEA restricting the number of embryos transferred to three. However, multiple pregnancy rates remain high with all the accompanying complications. The most recent HFEA report1 showed that when four or more fertilized eggs were available, the transfer of three embryos did not result in improved pregnancy rates compared with the elective transfer of two embryos. However, the incidence of triplets or higher order multiple births decreased considerably when two embryos were replaced. The British Fertility Society advocates the transfer of a maximum of two embryos as a measure of good practice. Other factors also have considerable impact on the cumulative pregnancy and live birth rates. These include the type of stimulation protocol used, the total number of oocytes retrieved and fertilized, the stage at which embryos are transferred, the number of surplus embryos available for cryopreservation, luteal phase support, and the number of attempts of ART procedures that a couple undergo. Detailed discussion is beyond the scope of this paper and the reader should consult specialist textbooks for further information. ANTENATAL COMPLICATIONS OF ART A large series2 reported no increase in the spontaneous miscarriage rate following IVF in comparison with natural conceptions. However, a higher incidence of multiple pregnancy, vaginal bleeding and hypertension requiring hospitalization were reported.3 Even among IVF singleton pregnancies, there was a significantly increased incidence of intrauterine growth restriction, placenta praevia and preterm delivery. These obstetric risks may reflect the women’s history of infertility and a relatively high incidence of a poor obstetric history. In-vitro fertilization mothers may have a higher incidence of pregnancy-induced hypertension, premature labour, labour induction and preterm delivery4, and multiple pregnancies have a higher prevalence of pre-eclampsia. Comparison of singleton IVF pregnancies with matched controls showed a longer first stage of labour, greater intrapartum blood loss and a trend towards a higher caesarean delivery than controls.5 Twin IVF pregnancies were comparable to naturally conceived twins in their mean gestational age at delivery, rates of induction of labour and mode of delivery. Women who conceived following oocyte donation, especially with a history of ovarian failure, should be considered as ‘high risk’. Analysis of 232 ovum donation pregnancies reported a higher risk of pregnancyinduced hypertension and postpartum haemorrhage, as well as an increased incidence of ‘small for gestational age’ infants and an operative delivery rate of 85%.6 Retrospective comparison of ICSI pregnancies with matched IVF controls showed similar early pregnancy fetal loss and multiple pregnancy rates.
303
More recently, pregnancies resulting from the transfer of fresh or frozen conventional IVF or ICSI were compared.7 The frozen ICSI group showed a significantly higher miscarriage rate than the frozen conventional IVF patients. Other complications relating to multiple pregnancy and prematurity will be discussed in the next section.
PERINATAL AND PAEDIATRIC OUTCOME OF ART Multiple pregnancy and prematurity An increase in twinning and triplet rates in developed countries such as England and Wales, Germany, The Netherlands, Switzerland and others has been attributed to the higher proportion of mothers treated with ovulation-inducing hormones, and partially attributed to IVF. It is widely accepted that multiple pregnancies account for a disproportionately large share of adverse pregnancy outcomes8, including increased incidence of (very) low birth weight, perinatal and neonatal mortality, as well as infant death. The increased incidence of death and morbidity in twin as compared with singleton pregnancies has been attributed mainly to prematurity9 and to adverse outcomes associated with premature delivery such as hyaline membrane disease, hypocalcaemia, hypoglycaemia, hyperbilirubinaemia, small for dates, and low apgar scores. In one recent study10, the contribution of IVF on changes in the incidence of low birth weight, preterm delivery, and multiple birth over a 3-year period was substantial. The increased incidence of preterm delivery and low birth weight was partly related to multiple births, though an increase in preterm deliveries has also been seen in IVF singleton pregnancies.11 As indicated earlier, there is increasing evidence that transferring two embryos instead of three does not compromise of the chance of pregnancy, and this appears to reduce the risk of triplets. Experience worldwide appears to be similar. Other studies report a multiple pregnancy rate of 14.3% for double embryo transfers and 32.4% for triple embryo transfers, with no significant difference in the pregnancy rate if at least one good quality embryo was available for transfer. It may be that the outcome of IVF-conceived twin pregnancies is comparable with that of normally conceived twins in terms of duration of gestation, birth weight, perinatal death, perinatal morbidity and incidence of congenital malformations.11 However, earlier evidence suggests that ART twin pregnancies have a higher incidence of preterm deliveries and need more neonatal intensive care when compared with matched control twin pregnancies.12 Interestingly, for both singleton and twin pregnancies obtained with IVF, the incidence of caesarean section is increased.11 This may in part be a reflection of the generally held medical perception of ART pregnancies being ‘precious’ and
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Current Paediatrics
hence a lower threshold for intervention by obstetricians, but may also indicate a higher complication rate necessitating operative delivery. Perinatal mortality/morbidity Early follow-up studies suggest that the still birth and perinatal mortality rates following IVF are comparable with national maternal age-standardized rates.3 In-vitro fertilization conceived twins have comparable perinatal mortality rates to their spontaneously conceived controls.11 Singleton IVF pregnancies are reported to have significantly worse perinatal outcome in comparison to spontaneously conceived pregnancies, mainly because of the increased rate of preterm birth.11 Other workers13 have found a doubling of the premature birth rate in singleton post infertility pregnancies when compared with normal controls, with an increased mortality rate. In-vitro fertilization infants may have a lower mean birth weight, more frequent occurrence of low birth weight, and a shorter gestation. Additionally, these infants may have longer hospitalizations, more days of oxygen therapy and continuous positive airway pressure, as well as increased prevalence of respiratory distress syndrome, patent ductus arteriosus, and sepsis.4 The same study concluded that couples who underwent IVF appear to be at increased risk of having low birth weight and preterm infants, but multiple gestations accounted for most of the neonatal morbidities. Births following ICSI treatment or resulting from the transfer of cryopreserved embryos did not differ from their respective controls.14,15 It is logical to assume that women with infertility problems are likely to have an increased incidence of pelvic or, for that matter, systemic pathology to account for their subfertile/infertile status. It therefore follows that such women having achieved a pregnancy would be susceptible to an increase in complication rates. Indeed, it has been reported that women with a past medical history of infertility, whether treated or untreated, may have a significantly increased risk of perinatal death.16 The same study showed that women with untreated infertility are at increased risk of perinatal death and any association with multiple births did not explain this finding. The same was true of women with treated infertility; the risks of associated multiple births explained some but not all of this excess. The authors advocate that at antenatal booking, a history of infertility, irrespective of treatment, should be sought due to the significantly increased risk of perinatal death. INCIDENCE OF CANCER It is important for potential parents utilizing ART, especially IVF and ICSI, to be counselled on the likely outcome of their unborn children’s health, especially any life-threatening illnesses such as cancer. There have been case reports17 of paediatric tumours in children conceived by IVF. For example, two children
12 and 18 months of age developed hepatoblastoma and clear cell carcinoma of the kidney. A possible association between IVF and paediatric malignancies has been suggested. However, ART are not generally considered to be associated with an increased rate of paediatric malignancies. Recent studies18 did not find any significantly increased incidence of cancer in children conceived using IVF and related procedures in comparison with the general population. Larger studies are needed to reach definite conclusions. IN-VITRO FERTILIZATION/ ICSI AND CONGENITAL ABNORMALITIES No increase in the malformation rate has been noted in children born following conventional IVF.3 Intracytoplasmic sperm injection, which was first successful in 1992, enabled men who had previously been diagnosed with severe male factor infertility, the chance to have their own genetic children and pass their genes on to their own progeny; an event that may not have been possible just a few years ago. This raises certain questions about the genetic constitution of any resulting pregnancies. Following ICSI, the quality of the sperm used may adversely affect the chromosome constitution of the resulting embryo.19 This particular case report utilized fluorescence in-situ hybridization (FISH) to determine any chromosomal abnormalities in embryos prior to implantation. An infertile couple with severe male infertility and endometriosis underwent two ICSI cycles with husband’s sperm and one IVF cycle with donor sperm. Pre-implantation genetic diagnosis with FISH showed that all the embryos derived from the cycle in which donor sperm was used were chromosomally normal, whereas 82% of embryos derived from cycles in which the husband’s sperm was used were chromosomally abnormal. It was concluded that paternal factors, thought to be derived from the paternal centrosome, could have contributed to the numerical chromosomal abnormalities and may, in turn, have predisposed to implantation failure. It is possible that they would be manifested as congenital abnormalities that present to the paediatrician. The cycle in which donor sperm was used resulted in an ongoing pregnancy. However, short- and long-term follow-up data on children born by ICSI have thus far been encouraging. One recent study14 showed no difference in the incidence of multiple pregnancies and perinatal outcome between standard IVF and ICSI. Furthermore, no major malformations were noted. In another retrospective follow-up study20, 132 children born after IVF and 120 after ICSI were analysed. No differences were found between the two groups for early embryonic development and obstetric outcome. The congenital malformation rate was 3% after IVF and 1.7% after ICSI. In both groups, the rate of women undergoing prenatal chromosomal diagnosis was low (30%). A 7-year prospective follow-up study21 of 1987 -
Assisted reproduction children born after ICSI compiled data on karyotypes, congenital malformations, growth parameters and developmental milestones. Prenatal diagnosis, as well as physical examination of the children at 2 months, 1 year and 2 years, was performed. The subgroups examined were children born after ICSI with ejaculated, epididymal and testicular spermatozoa. The Belgian group did not find any specifically higher incidence of malformations in any subgroup. One condition that does appear to be directly associated with ICSI is hypospadias. In over 1000 babies born after ICSI, seven cases of hypospadias were identified with an expectation in the general population of around two.22 Hypospadias appears to be associated with paternal subfertility so a link with ICSI is possible. The same study showed an increased risk of abnormalities in babies born after ICSI compared with babies born without the use of fertility treatment. However, this was mainly due to conditions associated with multiple or premature births, rather than the ICSI treatment itself. Couples requiring ICSI appear to have an increased incidence of chromosomal disorders and this appears to manifest itself as a low implantation rate.23 The risk of transmitting chromosomal aberrations can be minimized by karyotyping potential parents, pre-implantation genetic diagnosis and prenatal fetal karyotyping. There is also the long-term risk of transmitting fertility problems to the offspring. So far, about 20 000 babies have been born worldwide through ICSI in the last decade, and the vast majority of these are healthy normal children. Since ICSI is still a relatively new procedure, further follow-up studies are required. Potential parents may be reassured that, generally, there appears to be no higher incidence of major congenital malformations in children born after this procedure. CONCLUSION Overall, the paediatrician needs to be aware that probably the two most significant factors affecting assisted reproduction pregnancies are those associated with multiple pregnancy and prematurity. There does not appear to be any increased risk of major congenital abnormalities secondary to assisted reproduction procedures themselves, and the risk to children of developing malignancies does not appear to be greater than that of the general population. Women with a past medical history of infertility appear to have worse perinatal outcomes, possibly enhanced if they are oocyte recipients. Finally, ICSI does not appear to increase the incidence of major congenital malformations, although there is an increase in the incidence of hypospadias. Since it is still a relatively new procedure, potential parents should be made aware of the possible unforeseen complications and the risk of infertility of any resulting children.
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