Maryse Bonduelle

Report on a consecutive series of 581 children born after blastomere biopsy for preimplantation genetic diagnosis

BACKGROUNDnPreimplantation genetic diagnosis (PGD) and subsequently preimplantation genetic screening (PGS) have been introduced since 1990. The difference from the already existing in vitro fertilization (IVF) technology, using intracytoplasmic sperm injection (ICSI), was the embryo biopsy at day 3 after fertilization. Although healthy children post-PGD/PGS have been born, the question of whether embryo biopsy could have any harmful effects has to be studied on large series in a prospective manner.nnnMETHODSnA prospective cohort study was undertaken from 1992 until 2005, using the same approach as for the follow-up of IVF and ICSI children conceived in the same centre. Questionnaires were sent to physicians and parents at conception and at delivery. Children were examined at 2 months of age by trained clinical geneticists whenever possible.nnnRESULTSnData collected on 581 post-PGD/PGS children showed that term, birthweight and major malformation rates were not statistically different from that of 2889 ICSI children, with overall rates of major malformation among these post-PGD/PGS and ICSI children being 2.13 and 3.38%, respectively (odds ratio [OR]: 0.62; exact 95% confidence limits [95% CL]: 0.31-1.15). However, the overall perinatal death rate was significantly higher among post-PGD/PGS children compared with ICSI children (4.64 versus 1.87%; OR: 2.56; 95% CL: 1.54-4.18). When stratified for multiple births, perinatal death rates among PGD/PGS singleton and ICSI singleton children were similar (1.03 versus 1.30%; OR: 0.83; 95% CL: 0.28-2.44), but significantly more perinatal deaths were seen in post-PGD/PGS multiple pregnancies compared with ICSI multiple pregnancies (11.73 versus 2.54%; OR: 5.09; 95% CL: 2.80-9.90). The overall misdiagnosis rate was below 1%.nnnCONCLUSIONSnEmbryo biopsy does not add risk factors to the health of singleton children born after PGD or PGS. The perinatal death rate in multiple pregnancies is such that both caution and long-term follow-up are required.

Mental and psychomotor development of 2-year-old children born after preimplantation genetic diagnosis/screening

BACKGROUNDnEmbryo biopsy is a new invasive procedure applied in ART for diagnostic purposes in preimplantation genetic diagnosis (PGD) or to increase pregnancy rate in preimplantation genetic screening (PGS). The objective of this study is to assess mental and psychomotor developmental outcomes in 2-year-old children born after PGD/PGS, intracytoplasmic sperm injection (ICSI) and natural conception (NC).nnnMETHODSnTwo-year-old PGD/PGS (n = 70), ICSI (n = 70) and naturally conceived (n = 70) singleton children were recruited. The participation rate in the NC group was 88.6% and 94.5% in both ART conception groups. The mental and psychomotor development of the children was assessed using the Dutch version of the Bayley Scales of Infant Development. The mothers were questioned about socio-demographic characteristics.nnnRESULTSnEven after controlling for socio-demographic variables, no differences were found between the three conception groups for the mental and psychomotor developmental outcomes. Moreover, an equal number of PGD/PGS, ICSI and NC children obtained scores within the mildly delayed, the normal and the accelerated performance category of the BSID-II-NL.nnnCONCLUSIONSnChildren conceived after PGD/PGS show similar mental and psychomotor developmental outcomes at age 2 to children conceived after ICSI or naturally.

Outcome of pregnancies after intracytoplasmic sperm injection and the effect of sperm origin and quality on this outcome

Abstract Objective: To describe the outcome of pregnancies obtained after intracytoplasmic sperm injection (ICSI) and the impact of the origin and quality of sperm used on this outcome. Design: Retrospective analysis. Setting: A tertiary referral center for assisted reproduction. Patient(s): Pregnant patients conceived after microinjection of ejaculated sperm (n = 1,427), epididymal sperm (n = 79), and testicular sperm (n = 93). Intervention(s): ICSI, epididymal sperm aspiration, and testicular biopsy. Main Outcome Measure(s): Stillbirth, prematurity, and early perinatal mortality. Result(s): The delivery rate of multiple births was 31.4%, and the preterm delivery rate was 25.6%. The prematurity rates in singletons, twins, and triplets were 9.9%, 56.7%, and 96.6%, respectively. The early perinatal mortality rate of the entire population was 26.1‰. In the ejaculated-sperm group, when the sperm was severely defective (group 1), 14 intrauterine deaths occurred (3.1%). In the second and third groups, in which sperm was moderately defective, there were 2 deaths and 1 death (0.6% and 0.4%), respectively. The difference between the number of deaths in group 1 vs. groups 2/3 was statistically significant. Conclusion(s): The rates of multiple pregnancies, preterm deliveries, low birth weight, and early perinatal mortality were higher after ICSI than after natural conception. In the ejaculated-sperm group, the rate of intrauterine death was higher in the severely defective sperm group than in the better-quality sperm groups.

Neonatal outcome of 724 children born after ICSI using non-ejaculated sperm

BACKGROUNDnSafety concerns have been expressed regarding the use of immature non-ejaculated spermatozoa for ICSI. Therefore, adverse health outcomes, birth parameters, major anomaly rates and chromosomal aberrations in children born after ICSI using testicular and epididymal sperm were investigated.nnnMETHODSnQuestionnaire data and results of physical examinations of 530 children born after ICSI with testicular sperm and of 194 children born after ICSI with epididymal sperm were compared with data on 2516 ICSI children born using ejaculated sperm.nnnRESULTSnBirth parameters, stillborn rates, prematurity rates and rates of low birthweight and very low birthweight were comparable between the non-ejaculated and the ejaculated sperm groups. The perinatal death rate was higher for twins but not for singletons in the non-ejaculated sperm group in comparison to the control cohort of children born using ejaculated sperm. A non-significant increase in major anomalies was reported in the non-ejaculated sperm group in comparison to the ejaculated sperm group. No more anomalies were observed in pre- and post-natal karyotypes from viable pregnancies established using non-ejaculated sperm versus ejaculated sperm.nnnCONCLUSIONnOverall neonatal health in terms of birth parameters, major anomalies and chromosomal aberrations in our large cohort of children born by the use of non-ejaculated sperm seems reassuring in comparison to the outcome of children born after the use of ejaculated sperm.

Are ICSI adolescents at risk for increased adiposity

BACKGROUNDnPuberty is a critical period for the development of cardio-metabolic disturbances, including a more central body fat distribution. It is still unclear if IVF and more specifically ICSI, can permanently and detrimentally affect body fat accumulation in the human offspring. Therefore, adiposity and body fat distribution in 14-year-old adolescents born after ICSI were investigated.nnnMETHODSnBody composition data, including anthropometry (weight, height and BMI), skinfold thicknesses (peripheral: triceps and biceps skinfolds; central: supra-iliacal and subscapular skinfolds; total: sum of the four skinfolds) and circumferences (waist, mid-upper arm) were compared between 217 ICSI singletons (116 boys, 101 girls) and 223 singletons (115 boys, 108 girls) born after spontaneous conception (SC). ICSI teenagers were part of a previously published ICSI cohort followed since birth; SC controls were recruited from schools in the surroundings.nnnRESULTSnAmong all boys, no differences in body composition measurements were found between the ICSI and SC group, taking into account confounding variables. In boys with more advanced pubertal stages, a significantly higher sum of peripheral skinfolds was found in the ICSI group compared with the SC group (difference 3.5 mm, 95% confidence interval 0.3-6.6). In girls, peripheral adiposity assessed by skinfolds and mid-upper arm circumference, and central adiposity assessed by skinfolds and waist circumference as well as total adiposity assessed by BMI, the sum of four skinfold thicknesses and skinfold-derived body fat percentage were significantly higher in the ICSI group compared with the SC group, taking into account confounding variables (all P< 0.05). Neither parental nor early life factors could explain the differences.nnnCONCLUSIONSnWe found that pubertal ICSI girls were more prone to central, peripheral and total adiposity compared with their SC counterparts. ICSI adolescents with advanced pubertal stages showed more peripheral adiposity. Continued monitoring of body fat patterns in adolescents born after fertility treatment is mandatory in order to assess their risk for developing obesity and its related adverse health effects in adulthood.

Neonatal follow-up of 995 consecutively born children after embryo biopsy for PGD

BACKGROUNDnOutcome data on children born after assisted reproduction treatments are important for both patients and health-care providers. The objective of this study was to determine whether embryo biopsy as performed in PGD has an impact on the health of infants up to 2 months of age.nnnMETHODSnA prospective comparative follow-up study of children born after PGD and children born after ICSI by collecting written reports and performing a physical examination at 2 months was performed. Auxological data at birth and physical findings up to 2 months of age were compared for 995 children consecutively live born after embryo biopsy (1994-2009) and for a control group of 1507 children born after ICSI with embryo transfer on Day 5.nnnRESULTSnNo differences regarding mean term, prematurity (term <32 w and <37 w), mean birthweight, very low birthweight (<1500 g), perinatal death, major malformations and neonatal hospitalizations in singletons and multiples born following PGD versus ICSI were observed. Compared with ICSI, fewer multiples born following PGD presented a low birthweight (<2500 g) (P = 0.005).nnnCONCLUSIONSnEmbryo biopsy for PGD does not introduce extra risk to the overall medical condition of newborn children. Multiples born following embryo biopsy appear to be at lower risk for low birthweight compared with multiples born following ICSI.

Blood pressure in ICSI-conceived adolescents

STUDY QUESTIONnDo young adolescents conceived by ICSI display a higher blood pressure than spontaneously conceived (SC) adolescents?nnnSUMMARY ANSWERnIn our study, 14-year-old male and female ICSI teenagers were not found to have increased blood pressure at rest.nnnWHAT IS KNOWN AND WHAT THIS PAPER ADDSnOnly limited data are available regarding the cardiovascular risk of children born after assisted conception and up till now, no data on the cardiovascular health in pubertal children conceived by ICSI have been published. In this study, resting blood pressure and blood pressure response to a psychological stressor were measured in a cohort of 14-year-old teenagers conceived by ICSI and compared the results with those of a group of SC peers.nnnDESIGNnIn this cross-sectional study, resting blood pressure measurements were available from 217 singleton ICSI children (116 boys, 101 girls) and 223 singleton control children born after spontaneous conception (115 boys, 108 girls). Continuous blood pressure measurements, performed during a psychological stress test, were available for only 67 ICSI and 38 SC children.nnnPARTICIPANTS AND SETTINGnThe study group comprised adolescents conceived by ICSI predominantly because of male factor infertility and they were part of a previously published cohort followed since birth; controls were a cross-sectional sample of peers born to fertile parents and recruited from comparable schools as those attended by the ICSI teenagers. Response rates were 56% (tested/reached) in the ICSI group and 50% (agreed/eligible) in the SC group, but information regarding health could be obtained in 63 and 72% of the ICSI and SC children, respectively.nnnMAIN RESULTS AND THE ROLE OF CHANCEnICSI girls had a comparable resting systolic (109 ± 9 mmHg) and diastolic (64 ± 6 mmHg) blood pressure in comparison with girls in the SC group (111 ± 9 mmHg, P = 0.2 and 66 ± 7 mmHg, P = 0.05), even after adjustment for age and height. After adjustment for current body characteristics, early life and parental background factors, systolic and diastolic blood pressure remained comparable in both groups. In ICSI boys, a slightly lower systolic (113 ± 10 mmHg), but comparable diastolic (64 ± 6 mmHg) resting blood pressure was found in comparison with the SC group (116 ± 9 mmHg; P = 0.04 and 65 ± 5 mmHg; P = 0.1). After adjustment for height and age, systolic and diastolic blood pressure were comparable in both groups (P = 0.7 and P = 0.6). After correction for current body characteristics, early life and parental factors, ICSI and SC boys still had comparable systolic (difference in ICSI versus SC: -1.1 mmHg; 95% CI: -3.8-1.6; P = 0.4) and diastolic (difference in ICSI versus SC: -1.2 mmHg; 95% CI: -3.2-0.7; P = 0.2) blood pressure measurements. In the small subsample of girls and boys with continuous blood pressure readings, the systolic and diastolic blood pressure response to the stress test was not significantly different between the ICSI and SC groups even after taking into account the baseline values.nnnBIAS, CONFOUNDING AND OTHER REASONS FOR CAUTIONnDespite the rather low response rate in the ICSI group and the fact that no information on current health status could be obtained from more than a quarter of the eligible comparison group, the non-participating analysis in the ICSI as well in the SC group did not reveal differences between participating and non-participating children regarding clinical characteristics. The negative results for the sub-analysis on blood pressure response to stress should be interpreted with caution, because these data were available for only a small number of children, and the analysis may be underpowered. This result can only rule out a large effect on blood pressure responsiveness to a psychological stressor. Although our sample size appears to be appropriate, our results need confirmation by others and in larger cohorts when more data become available.nnnGENERALIZABILITY TO OTHER POPULATIONSnOur results are the first described ever in ICSI offspring, born to parents suffering from predominantly male factor infertility.nnnSTUDY FUNDING/COMPETING INTEREST(S)nThis study was supported by research grants from Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Onderzoeksraad Vrije Universiteit Brussel and Wetenschappelijk Fonds Willy Gepts. Unconditional grants from MSD Belgium, Merck International, IBSA Institut Biochimique and Ferring International Center are kindly acknowledged.

Socio-emotional and language development of 2-year-old children born after PGD/PGS, and parental well-being

BACKGROUNDnThe objective of this study was to assess socio-emotional and language development in 2-year-old children born after preimplantation genetic diagnosis (PGD) and genetic aneuploidy screening (PGS), intracytoplasmic sperm injection (ICSI) and natural conception (NC) and to assess parental well-being.nnnMETHODSnParents of 2-year-old PGD/PGS (n = 41), ICSI (n = 35) and NC (n = 53) singleton children were recruited. The socio-emotional development of the children was assessed using the Child Behavioural Checklist (CBCL) and the Short Temperament Scale for Toddlers. Parental stress and health status was measured with the Parent Stress Index and the General Health Questionnaire. Language development was assessed with the McArthur Communicative Development Inventories.nnnRESULTSnNo differences were found for temperament, language development, parental stress or health status. The mothers in the PGD/PGS and ICSI group reported significantly fewer CBCL Total problems than their NC counterparts, whereas for the CBCL Externalizing problems, only the ICSI mothers reported fewer problems than their PGD/PGS and NC counterparts. Fathers in the ICSI group also rated their children as having fewer Externalizing and Total behavioural problems.nnnCONCLUSIONSnPGD/PGS conception does not adversely affect childrens socio-emotional and language development at age 2, nor did parents differ from ICSI and NC parents for parental stress and health status.

Growth and health outcome of 102 2-year-old children conceived after preimplantation genetic diagnosis or screening.

OBJECTIVEnThe major objective of this study was to determine whether the embryo biopsy procedure might cause growth restriction or affect health outcome of children.nnnSTUDY DESIGNnAuxological data and physical findings were compared at birth and age 2 for 102 children (70 singletons and 32 twins) born after PGD/PGS and 102 matched children born after intracytoplasmic sperm injection (ICSI) in a prospective study.nnnRESULTSnNo statistically significant differences regarding weight, height and head circumference standard deviation scores (SDS) at birth and at age two years were observed. At two years of age the mean BMI SDS tended to be lower in PGD/PGS children (p=0.058). PGD/PGS babies had been more often breastfed (p=0.013), but mostly during a shorter time. The prevalence of major as well as minor congenital anomalies, hospital admissions and surgical interventions was similar.nnnCONCLUSIONnChildren born after embryo biopsy applied in PGD/PGS present similar prenatal and postnatal growth and health outcome in the first two years of life compared to ICSI children. Up till now, PGD and PGS appear not to be associated with a higher risk for health problems.

Pubertal development in ICSI children

BACKGROUNDnTo date, information on the pubertal development of adolescents born after ICSI is scarce, since the very first cohort is only now reaching young adulthood. In this study, pubertal development at the age of 14 was characterized in a longitudinally followed cohort of ICSI-conceived teenagers and compared with that of a spontaneously conceived (SC) control group.nnnMETHODSnPubertal development was assessed by Tanner staging (breast, genital and pubic hair development) and age at menarche in 217 singleton ICSI-conceived children (116 boys, 101 girls) and 223 SC peers (115 boys, 108 girls). ICSI teenagers were part of a previously published cohort followed since birth; controls were a cross-sectional sample recruited from schools. Differences in pubertal development between ICSI and SC children were analyzed with logistic regression of current status data.nnnRESULTSnMean age at menarche was similar in ICSI and SC girls (13.1 ± 1.2 versus 13.1 ± 1.4 years; P = 0.8). Breast developmental at the age of 14 years was less advanced in ICSI females compared with SC females, even after adjustment for demographic (age, BMI), genetic (maternal age at menarche), social (maternal educational level) and early life factors (birthweight, gestational age and maternal parity) [odds ratio (OR) 0.5; 95% confidence interval (CI) 0.3-0.8]. After adjustment, genital development in the 14-year-old boys was comparable in the ICSI and SC groups (OR 1.1; 95% CI 0.7-1.8), pubic hair development was comparable in the ICSI and SC groups, for both males (OR 0.9; 95% CI 0.7-1.6) and females (OR 0.7; 95% CI 0.4-1.3).nnnCONCLUSIONSnWe found that pubertal development, characterized by menarche, genital development in males and pubic hair development in males and females, was comparable in the ICSI and SC groups. Breast developmental was less advanced in ICSI females compared with SC peers, even after adjustment for known potential confounders. In order to confirm that progression through subsequent stages of pubertal development occurs on a timely basis in ICSI teenagers, long-term follow-up studies up to adulthood are required.