1 Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, Göteborg, 2 Tornblad Institute, University of Lund and 3 Fertility Center Scandinavia, Carlanderska Hospital, Göteborg, Sweden
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Abstract |
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Key words: intracytoplasmic sperm injection/malformations
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Introduction |
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Previous reports have been reassuring regarding the outcome of children born after ICSI, showing no increase in major malformations (Bonduelle et al., 1994, 1995
, 1996a
, Bonduelle et al., b
, 1998a
; Liebaers et al., 1995
; Palermo et al., 1996
; Wennerholm et al., 1996
). The incidence of major malformations detected at birth or during the perinatal period in these studies was reported to range between 0.95% and 3.6%, not significantly different from that observed after conventional IVF or from that expected in the general population. A re-evaluation of some of these results has provided a less reassuring interpretation (Kurinczuk and Bower, 1997
): their re-analysis compared birth defects in the Belgian ICSI children cohort (n = 420) to 100 454 infants born in Western Australia and concluded that the odds ratio (OR) for major birth defects was higher after ICSI [OR 2.0; 95% confidence interval (CI) 1.42.9]. However, the authors cautioned about confounders, e.g. a lower maternal age, a lower multifetal pregnancy rate and a possible lower surveillance in the reference population. Recently, a statistically significant increase in sex chromosomal aberrations (0.83%) was reported in a total of 1082 prenatal tests in pregnancies after ICSI (Bonduelle et al., 1998b
). Methodological shortcomings in the previous studies such as small numbers and lack of proper controls also emphasize the need to collect data from other centres and proper control groups.
We have studied the rate of congenital malformations in a cohort of children born after ICSI using data from the medical records, the Swedish Medical Birth Registry (MBR) and the Registry of Congenital Malformations (RCM). A comparison has been made with all births in Sweden and also with births after conventional IVF during corresponding time periods.
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Materials and methods |
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The number of children born after ICSI as a function of sperm origin (ejaculated, epididymal or testicular spermatozoa) and the replacement of fresh or frozenthawed pre-embryos respectively is shown in Table I. Medical records were retrieved for all infants. These were also identified in the Swedish MBR and the RCM (Källen, 1987
) in order to find any diagnoses which were missing in the medical record. The MBR also allowed the calculation of the expected numbers of malformed infants from all births.
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A possible excess of genito-urinary defects, major cardiovascular defects and gastrointestinal defects in children conceived by ICSI was shown in the Australian study (Kurinczuk and Bower, 1997). Previous studies have shown an association between hypospadias and reduced paternal fertility, notably with paternal problems (Sweet et al., 1974
) and between oesophageal atresia and maternal infertility (Robert et al., 1993
).
A similar procedure was therefore performed for three specific conditions: hypospadias, congenital heart defects (excluding persistent ductus arteriosus [PDA]), and intestinal atresia. For these specific conditions, the expected number of cases was determined from the population and compared with the observed numbers using exact tests based on Poisson distributions. The observed/expected ratio represents an estimate of the risk ratio (RR).
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Results |
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Tables II (relatively serious malformations) and III (minor or variable anomalies) present the identified malformations, divided into those which had a malformation diagnosis in the MBR and those which were only identified from the medical records and/or RCM. The total number of infants with an identified anomaly was thus 87 (7.6%), 40 of which were mild or uncertain conditions. Only eight of the malformations not recorded in the MBR were severe enough to be reportable to the RCM, four of which had actually been reported. Tables II and III
also specify which infants were born in twin births.
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A few specific malformations appeared to exist in excess. There were seven infants with hypospadias but only six were identifiable in the MBR (one was mis-coded). The expected number of infants with hypospadias, stratifying for year of birth, delivery hospital, maternal age and parity, was 2.01. The relative risk (RR) was 3.0 (exact 95% CI 1.096.50).
Two infants with an intestinal atresia were identified in the MBR and two additional infants had intestinal atresia but were not identified in the MBR. The expected number of infants with intestinal atresia recorded in the MBR was 0.33.
There were eight infants with a cardiac diagnosis (disregarding PDA) registered in the MBR. The expected number of infants with such a diagnosis in the MBR was 9.6, stratified for year of birth, maternal age, parity and delivery hospital. When all sources were used, 15 infants with cardiac defects were identified (the expected number was seven or eight). Among them, five were serious (expected number two or three).
There were three infants with chromosome aberrations and one with a genetic syndrome (Nager syndrome). One further infant had a possible but unverified trisomy 13.
There were two further multi-malformed infants, one of which was diagnosed with Goldenhar syndrome.
Table IV compares the presence of major malformations among the 1008 ICSI infants and the 5446 infants born after conventional IVF (Bergh et al., 1999
). Among the latter, only infants reported to the MBR or RCM were included and a similar restriction was therefore made for the ICSI material. Some differences appeared to exist. Most notable perhaps was the complete absence of neural tube defects or hydrocephaly in the ICSI material. The difference in rates (14/5446 and 0/1008), however, may be random. The lower exact confidence limit of the OR was 0.85 (not significant). The rate of neural tube defects registered in Sweden was 5.5 per 10 000 and of hydrocephaly 1.6 per 10 000. The expected number of such defects among infants born after conventional IVF was thus 3.9 and after ICSI was 0.8. There thus seemed to be an increased risk of such defects after conventional IVF but this was not demonstrated after ICSI.
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The only other malformation with a reasonably high frequency was oro-facial clefts the rates were similar in ICSI and IVF and the OR was 0.73 (95% CI 0.194.26), thus not significant.
Prenatal diagnosis
During the study period, four pregnancies after ICSI were interrupted because of the presence of fetal abnormalities, which were detected by second trimester ultrasound scanning. These abnormalities included trisomy 18, polycystic kidney disease and acrania (two cases).
As a routine, all patients with singleton pregnancies were offered an early amniocentesis for karyotyping, but it was not compulsory. Prenatal karyotyping was performed on 149 fetuses (13.1%). Abnormal results were found in four cases (2.7%). One singleton was a trisomy 18 and the parents chose to terminate the pregnancy in this case. Two were familial structural anomalies inherited from the father. One twin had an unbalanced translocation (see Table II).
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Discussion |
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The present study illustrates the problems in evaluating data obtained by screening of medical records for selected patients, e.g. infants born after IVF or ICSI. Rates of malformations obtained in this manner are difficult to compare with rates determined, for instance, from population registers (Lancaster, 1987). We found that a substantial number of congenital malformations were not included in the MBR and if data from medical record screening had been compared with rates from the MBR, the malformation risk associated with ICSI would have been exaggerated. Even after restriction to conditions identified in the registry, however, an excess risk was seen in children born after ICSI, amounting to 75% [i.e. OR 1.75 (95% CI 1.192.58)]. This excess risk can to a large extent be explained by conditions associated with multiple and premature birth, notably PDA and undescended testicle. It is also plausible that paediatric examination and recording of data concerning infants born after IVF and ICSI may be more detailed than for the average baby.
There is one condition which seems clearly over-represented among infants born after ICSI, namely hypospadias. This condition has been associated with reduced parental fertility (Källen et al., 1991) and notably with paternal problems (Sweet et al., 1974
). An association with ICSI is therefore plausible. Hypospadias has also been associated with progestin exposure during organogenesis (Harris, 1990
). Progesterone or progestins are often given after IVF treatment as luteal phase support. This association is probably due to confounding from the major reason for progestin therapy, bleeding in early pregnancy, an association seen irrespective of whether progestins have been used or not (Källén et al., 1992
). The apparently higher frequency of hypospadias after ICSI than after conventional IVF supports the explanation that the association between hypospadias and ICSI is due to confounding by paternal subfertility.
When specific malformations were compared between infants born after ICSI and after conventional IVF, there was an apparent lack of neural tube defects and hydrocephaly observed among the former but an over-representation among the latter, even though this difference may be random. These conditions are associated with twinning, and the rate of twin pregnancies in the conventional IVF material is higher (27%) than in the ICSI material (20%). It is, however, also possible that neural tube defects are specifically related to female infertility, as has been repeatedly suggested although never proven (cf. review by Elwood et al., 1992).
The crude increased rate of malformation in ICSI depends mainly on the presence of conditions related to prematurity and multiple births (e.g. PDA, undescended testicle). The only specific effect is seen on hypospadias which may be due to an association between paternal subfertility and hypospadias.
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Acknowledgments |
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Notes |
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References |
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Submitted on September 6, 1999; accepted on December 13, 1999.