Cognitive development of 12 month old Greek infants conceived after ICSI and the effects of the method on their parents

BACKGROUND: ICSI is widely used as a method of assisted reproduction in Greece. Research shows that children conceived after the application of ICSI develop normally. However, Bowen et al. (1998) reported that children conceived after ICSI had lower scores in the Mental Development Index (MDI) of the Bayley Scales of Infant Development compared with infants conceived naturally or by standard IVF treatment. This finding raised concerns about the effects of ICSI on infants' cognitive development. The aim of the present study was twofold. First to compare the cognitive development of Greek infants conceived after ICSI treatment to a control group of infants conceived after IVF treatment and to a further control group conceived naturally (NC). Second, to investigate the psychological effects of ICSI compared to IVF on Greek parents. METHODS: The Bayley Scales of Infant Development were employed to assess cognitive development of infants. A 37 item semi-structured interview was devised to obtain demographic information and to assess and compare the psychological effects of ICSI and IVF on parents. RESULTS: The mental development of infants in all three groups was within the normal range (ICSI 101.4, IVF 95.7, NC 98.9). The differences between the three groups were not statistically significant. The duration of pregnancy and the birthweight differed in the three groups. Furthermore, mothers in the IVF and the ICSI groups experienced anxiety during pregnancy. IVF mothers differed in the mode of delivery and a smaller number of these mothers breastfed their infants. CONCLUSIONS: This study has shown that Greek infants, born after the application of ICSI, have mental and motor scores within the normal range. With regard to the psychological effects, it appears that mothers in the ICSI and IVF groups experience greater anxiety during their pregnancies than those in the NC group.     

The influence of assisted reproduction on family functioning and children's socio-emotional development: results from a European study

BACKGROUND: ICSI is used with increasing frequency, but there is less information about the children born following this method of assisted reproduction than other forms of IVF. Some authors have suggested that it may contribute to more family stress than IVF. METHODS: ICSI conceived children were compared with IVF conceived children and naturally conceived (NC) controls. They were selected in five European countries: Belgium, Denmark, Greece, Sweden and the UK, and seen for psychological testing and a paediatric examination when they were 5 years old. In all countries, except Greece, mothers and fathers were asked to complete questionnaires about parental well-being, family relationships, parenting and child behaviour. RESULTS: Very few differences were found between the ICSI and NC group or the ICSI and IVF group. The only significant differences were that mothers in the ICSI conceived group reported fewer hostile or aggressive feelings towards the child and higher levels of commitment to parenting than the mothers of NC children. CONCLUSIONS: The study confirms the results of previous work with IVF families. This should be encouraging for families using these techniques in the future.     

A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception

BACKGROUND: Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. METHODS: 540 ICSI conceived 5-year-old children from five European countries were comprehensively assessed, along with 538 matched naturally conceived children and 437 children conceived with standard IVF. RESULTS: Of the 540 ICSI children examined, 63 (4.2%) had experienced a major congenital malformation. Compared with naturally conceived children, the odds of a major malformation were 2.77 (95% CI 1.41-5.46) for ICSI children and 1.80 (95% CI 0.85-3.81) for IVF children; these estimates were little affected by adjustment for socio-demographic factors. The higher rate observed in the ICSI group was due partially to an excess of malformations in the (boys') urogenital system. In addition, ICSI and IVF children were more likely than naturally conceived children to have had a significant childhood illness, to have had a surgical operation, to require medical therapy and to be admitted to hospital. A detailed physical examination revealed no further substantial differences between the groups, however. CONCLUSIONS: Singleton ICSI and IVF 5-year-olds are more likely to need health care resources than naturally conceived children. Assessment of singleton ICSI and IVF children at 5 years of age was generally reassuring, however, we found that ICSI children presented with more major congenital malformations and both ICSI and IVF children were more likely to need health care resources than naturally conceived children. Ongoing monitoring of these children is therefore required.     

Matched follow-up study of 5 8-year-old ICSI singletons: child behaviour, parenting stress and child (health-related) quality of life

BACKGROUND: Psychosocial follow-up of ICSI children is scarce. We compared child behaviour, parenting stress and quality of life for singletons aged 5-8 years born after ICSI, IVF and natural conception (NC). METHODS: All singletons born between June 1996 and December 1999 after ICSI in the Leiden University Medical Center were invited (n = 110). Matched singletons born after IVF and NC were recruited. Parents completed the Child Behaviour Checklist (measures problem behaviour), the Parenting Stress Index (Nijmeegse Ouderlijke Stress Index) and two quality of life questionnaires (Dux25 and TACQOL). Children completed the Dux25 Child form. RESULTS: Eighty-seven ICSI children (79%), 92 IVF children (73%) and 85 NC children enrolled. Prevalence of behavioural disorders-as reported by the parents-was comparable in the three groups. Three of 87 ICSI children had autism or an autistic spectrum disorder (ASD). Problem behaviour scores were similar for ICSI and NC children; IVF children (mainly girls) scored less problem behaviour (P < 0.05) and their scores were less often in the (borderline) clinical range. Parenting stress was similar for ICSI and IVF, but lower for NC than ICSI parents, mainly on the child scale. Quality of life scores were similar in the three conception groups. CONCLUSIONS: Prevalence of autism/ASD seemed higher after ICSI, but this unexpected finding should be confirmed by future studies with larger group sizes. ICSI parents experienced more stress than NC parents, although selection bias cannot be ruled out. The majority of ICSI singletons assessed at age 5-8 years showed a normal psychosocial well-being.     

Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF.

BACKGROUND: Over the past decade attention has been increasingly focused on the long-term health effects of assisted reproductive technologies (ART), such as IVF, in both women and their offspring. To determine the risk of cancer in children conceived by IVF we used a large population-based historical cohort that was initially designed to examine the risk of gynaecological disorders in women who underwent IVF. METHODS: Children were included in the exposed group if they were conceived by IVF or other related fertility techniques (n=9484). The unexposed group consisted of 7532 children whose mothers were diagnosed with subfertility disorders but who were conceived naturally. All cohort members were asked to complete a mailed questionnaire that inquired about reproductive variables and cancer in the offspring (response rate 66.9%). RESULTS: During an average follow-up period of 6.0 years, 16 cancers were observed in the exposed and unexposed group combined, whereas 15.5 were expected [standardized incidence ratio (SIR) = 1.0; 95% confidence interval (95% CI) 0.6-1.7]. A direct comparison between children conceived after ART and naturally conceived children revealed no increased risk for childhood malignancies [risk ratio (RR) = 0.8; 95% CI 0.3-2.3]. CONCLUSIONS: Despite the small numbers of observed cancer cases, these findings demonstrate that children conceived by ART have no greatly increased risk of cancer during childhood compared with the general population and the internal reference group.     

Paternal sperm concentration and growth and cognitive development in children born with a gestational age more than 32 weeks after assisted reproductive therapy

BACKGROUND: A possible impact of paternal sperm quality on the outcome in children born after assisted reproductive technologies, especially ICSI, has been discussed. The objective of this study was to assess whether sperm concentration has any influence on growth and cognitive development in children born with a gestational age more than 32 weeks after ICSI or IVF. METHODS: Singleton children born after ICSI (n = 492) or IVF (n = 265) from five European countries were examined at age 5 years. The ICSI group was divided into five subgroups according to paternal sperm origin and sperm concentration: (1) epididymal and testicular sperm group, (2) ejaculated sperm < 1 x 10(6)/ml, (3) ejaculated sperm 1-4.99 x 10(6)/ml, (4) ejaculated sperm 5-19.99 x 10(6)/ml and (5) ejaculated sperm > or = 20 x 10(6)/ml. The IVF group was divided into two subgroups: (1) < 20 x 10(6)/ml and (2) > or = 20 x 10(6)/ml. Growth parameters at birth and age 5 were evaluated. Cognitive development was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised. RESULTS: No significant difference was found for gestational age, birth weight and birth weight standard deviation scores (SDS) between the ICSI and IVF sperm groups. No significant difference in height and weight at age 5 or SDS weight or height or BMIs at age 5 was found. There was no significant difference in total intelligence quotient (IQ)--performance or verbal IQ--between the groups. CONCLUSION: We found no indication that growth and cognitive development in ICSI and IVF children differed depending on paternal sperm concentration.     

Congenital malformations in 4224 children conceived after IVF

BACKGROUND: The percentage of children born after IVF will continue to increase due to demographic changes such as increasing maternal age and new developments in assisted reproduction techniques. IVF conceptions may carry an increased risk of congenital malformations. METHODS: We compared overall and specific congenital malformation rates calculated for IVF children (n = 4224) and naturally conceived children (n = 314 605), using records from the same Dutch national database for the years 1995 and 1996 and controlling for confounding maternal factors. RESULTS: The overall crude odds ratio (OR) for the risk of any malformation for IVF children compared with naturally conceived children was 1.20 [95% confidence interval (CI): 1.01-1.43]. After correction for differences in maternal age, parity and ethnicity between the IVF and control population the OR was 1.03 (95% CI: 0.86-1.23). The crude OR for IVF children appeared higher for the cardiovascular organ system and for several specific minor congenital malformations. However, these could be chance findings due to comparison of many malformation categories or may result from remaining differences in ascertaining malformations between IVF and naturally conceived children. CONCLUSIONS: The small increase in overall congenital malformations observed in the IVF children appears to be attributable to differences in maternal characteristics and not to any aspect of the IVF procedure.     

'Vanishing embryo syndrome' in IVF/ICSI

BACKGROUND: In a Danish population-based cohort study assessing the risk of cerebral palsy in children born after IVF, we made some interesting observations regarding 'vanishing co-embryos'. METHODS and RESULTS: All live-born children born in Denmark from 1 January 1995 to 31 December 2000 were included in this analysis. The children conceived by IVF/ICSI (9444) were identified through the IVF Register, the children conceived without IVF/ICSI (395 025) were identified through The Danish Medical Birth Register. Main outcome measure was the incidence of cerebral palsy. Within the IVF/ICSI children we found indications of an increased risk of cerebral palsy in those children resulting from pregnancies, where the number of embryos transferred was higher than the number of children born. CONCLUSIONS: The association between vanishing embryo syndrome and incidence of cerebral palsy following IVF requires further investigation in larger, adequately powered, studies.     

Hospital care utilization of IVF/ICSI twins followed until 2-7 years of age: a controlled Danish national cohort study

BACKGROUND: IVF/ICSI twins are likely to have a higher risk of prematurity associated with higher morbidity. The aim of this study was to assess the use of hospital care resources in IVF/ICSI twins on data retrieved until 2-7 years of child age. METHODS: National controlled cohort study on hospital admissions and surgical interventions in 3393 IVF twins, 10,239 spontaneously conceived twins and 5130 IVF singletons born between 1995 and 2000 in Denmark. Cross-linkage of data from the Danish IVF Registry and the National Patient Registry enabled us to identify children who were admitted to hospital or underwent an operation. RESULTS: The frequency of hospitalized children was 69.8, 69.6 and 49.8%, and of children who underwent a surgical intervention 10.6, 11.2 and 8.5% in IVF/ICSI twins, control twins and IVF/ICSI singletons respectively. Odds ratios (OR) (95% confidence intervals) of hospitalization in IVF/ICSI twins versus control twins and IVF/ICSI singletons were 1.04 (0.96, 1.14) and 2.44 (2.22, 2.63) and OR adjusted for year of birth, maternal age and parity were 1.00 (0.91, 1.11) and 2.38 (2.17, 2.63) respectively. Also for term birth infants, IVF/ICSI twins were more likely to be hospitalized than IVF/ICSI singletons: adjusted OR 1.37 (1.22, 1.51). Similar risk of a surgical procedure was observed in IVF/ICSI versus control twins. However, IVF/ICSI twins more often underwent a surgical intervention than IVF/ICSI singletons: adjusted OR 1.26 (1.08, 1.47). This risk disappeared when restricted to term infants: adjusted OR 1.00 (0.81, 1.22). Different sex IVF/ICSI and control twins had equal risk of admissions and surgical interventions, and ICSI children had the same risk as children born after conventional IVF. CONCLUSIONS: Though the use of hospital care resources was similar in IVF/ICSI and control twins, the over-use in IVF/ICSI twins versus IVF/ICSI singletons adds to the arguments for implementing elective single embryo transfer as our standard procedure.     

Malformation rate and sex ratio in 412 children conceived with epididymal or testicular sperm

BACKGROUND: Follow-up studies of children conceived after ICSI using epididymal or testicular sperm are important due to a still more extensive use of immature male germ cells for ICSI. It is, however, difficult to evaluate the potential risks of malformations of children born after ICSI, overcoming the natural fertilization processes, due to methodological limitations. METHODS: Follow-up study including all children born in Denmark and Norway following ICSI in Denmark, using epididymal or testicular sperm, was done. A questionnaire was sent to the parents between 3 months and 7 years after delivery. RESULTS: Of 341 couples, 329 returned the questionnaire giving a response rate of 96.5%. The study included 412 children, 225 girls and 187 boys, giving a sex ratio (males/males + females) of 45.4% compared with 53.1% in Danish children conceived after conventional IVF without ICSI (P < 0.005). Among a total of 14 (3.4%; 95% confidence interval (CI): 1.9%-5.7%) major malformations, three boys with hypospadias were the most remarkable finding (1.6%; 95% CI: 0.33-4.7%). CONCLUSIONS: An increased frequency of hypospadias in the male offsprings was seen compared with the general population. Apart from this, no increased major malformation rate was detected in ICSI children conceived with epididymal or testicular sperm when compared with malformation rates for IVF or spontaneously conceived children reported in the literature. The sex ratio was significantly lower for ICSI children conceived with epididymal or testicular sperm when compared with children conceived with conventional IVF.     

Perinatal complications of assisted reproduction

The main perinatal complications of assisted reproduction include congenital malformation, chromosomal aberrations, multiple pregnancy, and prematurity. Earlier studies and in vitro fertilization (IVF) registries showed that there was no increased incidence of congenital malformations in children conceived by IVF/intracytoplasmic sperm injection (ICSI). However, a large Australian study has found that by one year of age, the incidence of congenital malformations in IVF/ICSI children is increased in comparison with those naturally conceived. Several investigators found a slight but increased risk of chromosomal aberrations in ICSI children. Multiple pregnancy is a major cause of increased perinatal mortality due to increased incidence of both prematurity and congenital malformations. Even in singleton pregnancies conceived by assisted reproductive technologies, the risk of prematurity and newborns small for gestational age is increased. In this article, recently published work on perinatal complications associated with assisted reproductive technologies is reviewed.     

Maternal and neonatal outcomes in dichorionic twin pregnancies following IVF treatment: a hospital-based comparative study

Aim: To compare maternal, and neonatal outcomes in IVF/ICSI and spontaneously conceived dichorionic twin pregnancy. Method: We collected data regarding dichorionic twin pregnancies following in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI, n=162) with the transfer of fresh embryos as well as data regarding spontaneously conceived pregnancies (n=213) delivered after 28 weeks of gestation at the Department of Obstetrics and Gynecology, Renmin Hospital in Wuhan in the years of 2010-2013. We then compared maternal and neonatal outcomes between IVF/ICSI and spontaneous dichorionic twin pregnancies, with a subgroup analysis separating traditional IVF from ICSI pregnancies. Odds ratios (OR) for associations between IVF/ICSI and pregnancy outcomes were adjusted for maternal factors. Results: The mean maternal age and the percentage of primiparous women were significantly higher in the IVF/ICSI group. Multivariate analysis revealed that maternal outcomes were comparable in both groups with/without adjustment for maternal age and parity. However, IVF/ICSI twins were less likely to have birth weight discordance than those spontaneously conceived (unadjusted OR=0.526, 95% CI 0.297-0.932; adjusted OR=0.486, 95% CI 0.255-0.856). In subgroup analyses, these associations were confirmed in the IVF (adjusted OR=0.496, 95% CI 0.265-0.926), but not in the ICSI group (adjusted OR=0.500, 95% CI 0.139-1.807). Conclusion: IVF/ICSI treatment was not a risk factor for adverse maternal neonatal outcomes, but the risk for birth weight discordance is lower among IVF/ICSI twins.     

Morbidity in a Danish national cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 IVF/ICSI singletons: health-related and social implications for the children and their families

BACKGROUND: There is a lack of knowledge on child health as well as family well-being in IVF/ICSI twins. METHODS: These data originated from questionnaires completed by mothers taking part in a national cohort study of twin and singleton births occurring in Denmark in 1997. The overall response rate was 83%. The three cohorts consisted of all IVF/ICSI twin children (n = 472), all IVF/ICSI singletons (n = 634) and all non-IVF/ICSI twin children (n = 1132) born in Denmark in 1997. RESULTS: No major differences in physical health were observed between IVF/ICSI twins and non-IVF/ICSI twins. Compared with IVF/ICSI singletons, more IVF/ICSI twins were admitted to a neonatal intensive care unit (NICU) (P < 0.01) and more had surgical interventions (P = 0.03) and special needs (P = 0.02), moreover they had poorer speech development (P < 0.01). Correspondingly, IVF/ICSI twin mothers rated their infant's general health poorer than IVF/ICSI singleton mothers did. All discrepancies between IVF/ICSI twins and singletons disappeared after stratification for birthweight except for NICU admissions and speech development. Multiple logistic regression analyses showed that both IVF/ICSI and non-IVF/ICSI twin parents experienced more marital stress [odds ratio (OR) 2.9, 95% CI 2.2-3.8] and that twins had more impact on the mother's life (OR 1.7, 95% CI 1.2-2.4) compared with singletons. Nevertheless, the only predictor of low divorce/separation risk was IVF/ICSI treatment. CONCLUSION: Our study indicates that physical health of IVF/ICSI twins is comparable with that of non-IVF/ICSI twins. However, physical health of IVF/ICSI twins is poorer and the implications for the families stronger compared with IVF/ICSI singletons.     

Follow-up of cognitive and motor development of 10-year-old singleton children born after ICSI compared with spontaneously conceived children

BACKGROUND: This is the first follow-up study of the cognitive, psychosocial, family-relational and medical development of ICSI children at ages 8 and 10. Second-wave study results on the cognitive and motor development of 10-year-old ICSI children are discussed and compared with the outcome at 8 years. METHODS: Developmental outcomes of 109 10-year-old singletons born through ICSI after at least 32 weeks of gestation were compared with those of 90 singletons of the same age born after spontaneous conception (SC). The outcomes were also compared with the outcomes of the children at age 8. RESULTS: 10-year-old ICSI children obtained total, verbal and performance intelligence scores comparable to those of SC children. No significant differences were found between ICSI and SC children regarding overall motor, manual and ball skills. ICSI children and girls appear to have better balance skills than SC children and boys, respectively. With regard to long-term follow-up, the IQ results of ICSI and SC children at age 10 appear to have converged (from slightly higher scores in the ICSI children at age 8), probably indicating a decreased effect of maternal educational level or stimulating home environment in the ICSI group over time. CONCLUSIONS: In this follow-up study, ICSI and SC children show a comparable cognitive and motor development until the age of 10. These findings are in line with those obtained at age 8.     

Developmental outcome at 2 years of age for children born after ICSI compared with children born after IVF

BACKGROUND: Since the introduction of ICSI in 1991, medical outcome studies on ICSI children have been performed, but few have addressed developmental outcome. Hence, this outcome was assessed by performing a standard developmental test on children born after ICSI as compared with children born after IVF, at the age of 2 years. METHODS: In a prospective study, the medical and developmental outcome of 439 children born after ICSI (378 singletons, 61 twins) were compared with those of 207 children born after IVF (138 singletons, 69 twins), at the age of 24-28 months. These children were part of a cohort of children followed since birth. Of children reaching the age of 24-28 months between May 1995 and March 2002, 44.3% (2375/5356) were examined by a paediatrician who was unaware of the type of treatment used for each couple. Of all the children born, 12.2% (439/3618) in the ICSI group and 11.9% (207/1738) in the IVF group underwent a formal developmental assessment using the Bayley Scale of Infant Development (mental scale) by a paediatrician blinded to the type of treatment. RESULTS: There was no significant difference in maternal educational level, maternal age, gestational age, parity, birthweight, neonatal complication rate or malformation rate at 2 years between ICSI and IVF singletons, or between ICSI and IVF twins. No significant difference was observed in the developmental outcome using the Bayley scale at the age of 24-28 months (raw scores or test age) between ICSI children or IVF children. A multivariate regression analysis for the singleton children indicated that parity, sex (boys had lower scores than girls) and age had a significant influence on the test result, but that the fertility procedure (ICSI versus IVF) did not influence the test result. ICSI children from fathers with low sperm concentration, low sperm motility or poor morphology had a similar developmental outcome to that of children from fathers with normal sperm parameters. There were no significant differences between the initial cohort and the group lost to follow-up, nor between the psychologically tested and the non-tested group for a number of variables such as maternal educational level, birthweight in singletons and neonatal malformation rate. Although only some of the cohort of ICSI children were evaluated, a representative sample of both ICSI and IVF children was compared. CONCLUSIONS: There is no indication that ICSI children have a lower psychomotor development than IVF children. Paternal risk factors associated with male-factor infertility were found not to play a role in developmental outcome.     

Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995 infants born after IVF (1983-1999)

BACKGROUND: To evaluate the safety of ICSI, this study compared data of IVF and ICSI children by collecting data on neonatal outcome and congenital malformations during pregnancy and at birth. METHODS: The follow-up study included agreement to genetic counselling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 months, after 1 year and after 2 years. 2840 ICSI children (1991-1999) and 2955 IVF children (1983-1999) were liveborn after replacement of fresh embryos. ICSI was carried out using ejaculated, epididymal or testicular sperm. RESULTS: In the two cohorts, similar rates of multiple pregnancies were observed. ICSI and IVF maternal characteristics were comparable for medication taken during pregnancy, pregnancy duration and maternal educational level, whereas maternal age was higher in ICSI and a higher percentage of first pregnancies and first children born was observed in the ICSI mothers. Birthweight, number of neonatal complications, low birthweight, stillbirth rate and perinatal death rate were compared between the ICSI and the IVF groups and were similar for ICSI and IVF. Prematurity was slightly higher in the ICSI children (31.8%) than in the IVF children (29.3%). Very low birthweight was higher in the IVF pregnancies (5.7%) compared with ICSI pregnancies (4.4%). Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI liveborn children and in 3.8% of the IVF children (P = 0.538). Malformation rate in ICSI was not related to sperm origin or sperm quality. The number of stillbirths (born > or =20 weeks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group. Total malformation rate taking into account major malformations in stillborns, in terminations and in liveborns was 4.2% in ICSI and 4.6% in IVF (P = 0.482). CONCLUSIONS: The comparison of ICSI and IVF children taking part in an identical follow-up study did not show any increased risk of major malformations and neonatal complications in the ICSI group.     

Androgen receptor CAG polymorphism (Xq11-12) status and human spermatogenesis: a prospective analysis of infertile males and their offspring conceived by intracytoplasmic sperm injection

We determined the association of androgen receptor (AR) (CAG)n lengths among fertile and infertile males and offspring conceived by intracytoplasmic sperm injection (ICSI). Assessment of (CAG)n repeats in the AR was performed in a Caucasian population by gene sequencing in fertile men (n=13), infertile men (n=64), boys conceived after ICSI (n=21), and boys conceived naturally (n=11). In the AZF region of the Y chromosome, a total of 22 STSs were analyzed by multiplex PCR; selected spermatozoa were also analyzed by fluorescent in situ hybridization (FISH) for chromosomes 18, 21, X, and Y. The average age was 43.7+/-7 yr for infertile, 44.8+/-7 yr for fertile men, and 5.0+/-0.5 yr for the children. The mean (CAG)n was 22.2+/-3 for the infertile men and 19.3+/-5 for fertile controls. There was a significant difference in CAG repeat length in the severely oligo-/azoo-spermic men vs. controls (p=0.02). An inverse correlation was evident between CAG length and semen parameters. For ICSI male children, the AR (CAG)n lengths were 21.4+/-3.2 vs. 20.8+/-3.4 for boys conceived naturally. While all peripheral karyotypes of fertile and infertile men were normal, de novo gonosomal abnormalities were observed in the ICSI offspring. The incidence of Y microdeletions was 1.6% in infertile men; all the ICSI sons had an intact Y chromosome. In conclusion, severely oligo- and azoospermic men had longer CAG repeat length than fertile controls, suggesting that certain AR gene mutations may have a negative effect on spermatogenesis. An increased incidence of de novo gonosomal abnormalities was found in the ICSI offspring when compared to children conceived naturally. Our assessment of the polymorphic region of the AR gene, in the absence of other specific genomic abnormalities, suggests that the fertility of children conceived by ICSI may be conserved.     

Assisted reproductive technologies and the risk of birth defects--a systematic review

BACKGROUND: The risk of birth defects in infants born following assisted reproductive technology (ART) treatment is a controversial question. Most publications examining the prevalence of birth defects in ICSI and IVF infants compared to spontaneously conceived infants have serious methodological limitations; despite this, most researchers have concluded that there is no increased risk. METHODS: We carried out a systematic review to identify all papers published by March 2003 with data relating to the prevalence of birth defects in infants conceived following IVF and/or ICSI compared with spontaneously conceived infants. Independent expert reviewers used criteria defined a priori to determine whether studies were suitable for inclusion in a meta-analysis. Fixed effects meta-analysis was performed for all studies and reviewer-selected studies. RESULTS: Twenty-five studies were identified for review. Two-thirds of these showed a 25% or greater increased risk of birth defects in ART infants. The results of meta-analyses of the seven reviewer-selected studies and of all 25 studies suggest a statistically significant 30-40% increased risk of birth defects associated with ART. CONCLUSIONS: Pooled results from all suitable published studies suggest that children born following ART are at increased risk of birth defects compared with spontaneous conceptions. This information should be made available to couples seeking ART treatment.     

First trimester biochemical screening for Down's syndrome in singleton pregnancies conceived by assisted reproduction

BACKGROUND: Serum biochemical markers [free betahCG (fbetahCG); pregnancy-associated plasma protein-A (PAPP-A)] used in first trimester Down's syndrome screening have not been fully investigated in pregnancies achieved by assisted reproduction techniques. We present data on pregnancies conceived by all types of assisted reproduction techniques, including pregnancies following ovum donation (OD) and a large sample by ICSI. METHODS: First trimester Down's syndrome screening was performed in 1054 normal singleton pregnancies: natural conception (n = 498), ovulation induction (OS, n = 97), IVF (n = 47), ICSI (n = 222) and OD (n = 190). RESULTS: No differences in maternal levels of fbetahCG and PAPP-A, measured by the Kryptor system, appeared between naturally conceived pregnancies (n = 498) and those obtained with assisted reproduction techniques (n = 556). Several differences were apparent when comparing fbetahCG levels between different technologies but PAPP-A levels only differed between OS and IVF pregnancies (P < 0.05). In a further small study, no differences were observed using frozen embryos (n = 37), preimplantation genetic diagnosis (n = 53) or sperm from testicular biopsy (n = 21). CONCLUSIONS: Data accumulated so far suggest that first trimester biochemical markers either do not need any adjustments (e.g. in pregnancies obtained after OS and ICSI), or have very little impact (e.g. IVF pregnancies) or no impact (e.g. OD pregnancies) on the false positive rates.     

Maternal serum alpha-fetoprotein and human chorionic gonadotrophin in pregnancies conceived after intracytoplasmic sperm injection and conventional in-vitro fertilization.

Data in the Caucasian population suggest that maternal serum alpha-fetoprotein (AFP) and unconjugated oestriol concentrations are reduced and human chorionic gonadotrophin (HCG) concentrations are elevated in pregnancies conceived after in-vitro fertilization (IVF), leading to a higher than expected Down's syndrome screen-positive rate. There are no previous reports on the serum marker values in pregnancies conceived after intracytoplasmic injection (ICSI). Between 1996 and 1998, we measured maternal serum total HCG and AFP concentrations between 15 and 20 weeks gestation in 42 in-vitro fertilization (IVF) pregnancies and 23 ICSI pregnancies with known normal outcome. The results were compared with that of 2799 naturally occurring singleton pregnancies who were known to have a normal outcome. Median AFP multiple of the median (MOM) in ICSI pregnancies was significantly reduced to 0.76 compared with both that of the controls and that of the IVF pregnancies. For the IVF pregnancies, median HCG MOM was elevated to 1.15, and median AFP MOM was reduced to 0.88 compared with the controls, but these differences were not statistically significant. In both the IVF and ICSI pregnancies the changes might result in a falsely high Down's syndrome risk. In particular, the reduced AFP concentration in ICSI pregnancies was substantial. If this preliminary finding is substantiated by other series, the appropriate adjustment needs to be made to allow for valid interpretation of the screen result and to avoid an unnecessarily high false positive rate.