M. Bonduelle

International Collaborative Study of Intracytoplasmic Sperm Injection–Conceived, In Vitro Fertilization–Conceived, and Naturally Conceived 5-Year-Old Child Outcomes: Cognitive and Motor Assessments

Objective. To date, very few studies have been conducted on the neurodevelopmental well-being of children conceived through intracytoplasmic sperm injection (ICSI). The limitations of these studies often include a lack of comparison with a demographically matched, naturally conceived (NC) group and the investigation of only very young children, with relatively small samples sizes. One study showed that there were no differences in IQ scores among ICSI-conceived, in vitro fertilization (IVF)-conceived, and NC children at 5 years of age. Unfortunately, psychomotor development was not assessed in that study. Because findings regarding these childrens cognitive and motor development are inconclusive, the aim of this study was to shed more light on the cognitive and motor development of 5-year-old ICSI-conceived children. Methods. A total of 511 ICSI-conceived children were compared with 424 IVF-conceived children and 488 NC controls. Children were recruited in 5 European countries, ie, Belgium, Denmark, Greece, Sweden, and the United Kingdom. Participation rates ranged from 45% to 96% in the ICSI and IVF groups and from 34% to 78% in the NC group. Cognitive and motor development was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) and McCarthy Scales of Childrens Abilities (MSCA) Motor Scale, respectively. The WPPSI-R consists of 2 major scales, ie, Verbal and Performance, each including 6 subtests. The 6 Performance Scale subtests are object assembly, geometric design, block design, mazes, picture completion, and animal pegs. The 6 Verbal Scale subtests are information, comprehension, arithmetic, vocabulary, similarities, and sentences. Scores on the Performance and Verbal Scale subtests are summed to yield the performance IQ (PIQ) and verbal IQ (VIQ), respectively. Scores on both the Performance Scale and the Verbal Scale yield the full-scale IQ (FSIQ). IQ scales have a mean score of 100 and a SD of 15. Each subtest has a mean score of 10 and a SD of 3. The MSCA consists of 6 scales, ie, Verbal, Perceptual-Performance, Quantitative, General Cognitive, Memory, and Motor Scale. In this study, only the Motor Scale was administered. This scale assesses the childs coordination during performance of a variety of gross- and fine-motor tasks. Leg coordination, arm coordination, and imitative action tests provide measures of gross-motor ability. Draw-a-design and draw-a-child assess fine-motor coordination, as revealed by the levels of hand coordination and finger dexterity. The mean score for this test is 50, with a SD of 10. Results. No differences were identified among ICSI, IVF, and NC children with respect to VIQ, PIQ, or FSIQ scores of the WPPSI-R. Furthermore, there were no differences between groups regarding the discrepancy between VIQ and PIQ scores. These results were not influenced by gender, country, or maternal educational level. However, in the subgroup of firstborn children with mothers who gave birth at an older age (33–45 years), NC children obtained significantly better VIQ and FSIQ scores than did children conceived through assisted reproductive technologies. These differences in VIQ and FSIQ scores between ICSI/IVF and NC children were relative, because NC children scored <1 IQ point higher than ICSI/IVF children. Therefore, these scores show no clinical relevance. For Verbal Scale subtests, variables such as age of the mother at the time of the birth, educational level of the mother, and gender and nationality of the child interacted with mode of conception, resulting in clinically irrelevant differences between scores for the ICSI/IVF and NC groups on the arithmetic, vocabulary, and comprehension subtests. For Performance Scale subtests, these same demographic factors interacted with mode of conception for the block design, object assembly, and animal pegs subtests, again resulting in clinically irrelevant differences among groups. In the 3 groups (ICSI, IVF, and NC), we observed equal numbers of children scoring below 1 SD from the mean on the WPPSI-R and the MSCA. Conclusions. This study includes a substantial number of children from several European countries. Apart from a few interaction effects between mode of conception and demographic variables, no differences were found when ICSI, IVF, and NC scores on the WPPSI-R and MSCA Motor Scale were compared. Nevertheless, the aforementioned interaction effects could indicate that demographic variables such as maternal age at the time of the birth and maternal educational level play different roles in the cognitive development of IVF and ICSI children, compared with NC children. Additional research is needed to explore and verify this finding. Previous studies revealed that ICSI children, in comparison with NC children, more frequently obtained scores below 1 SD from the mean on 3 subtests of the Performance Scale (object assembly, block design, and mazes) or showed a trend of 5.2% of ICSI children, compared with 2.5% of IVF children and 0.9% of NC children, obtaining a score below 1 SD from the mean, but those findings were not confirmed in this study. Here no differences were found among the 3 groups in the numbers of children scoring below 1 SD from the mean on the VIQ, PIQ, and FSIQ tests and the Verbal and Performance Scale subtests. Motor development results were somewhat more conclusive. There were no differences between the scores of ICSI, IVF, and NC children on the MCSA Motor Scale. No interaction effects were found between mode of conception and demographic variables, indicating that these results are not influenced by gender, nationality, maternal educational level, or maternal age at the time of the birth. Furthermore, equal proportions of children in all 3 groups scored below 1 SD from the mean. The results of this study are reassuring for parents who conceived through ICSI (or IVF). The findings indicate that the motor and cognitive development of their offspring is very similar to that of NC children. However, demographic factors such as maternal educational level and maternal age at the time of the birth might play different roles in the cognitive development of ICSI and IVF children, compared with NC children.

The type of culture medium and the duration of in vitro culture do not influence birthweight of ART singletons

STUDY QUESTIONnDoes the type of in vitro culture medium or the duration of in vitro culture influence singleton birthweight after IVF/ICSI treatment?nnnSUMMARY ANSWERnIn a comparison of two culture media, neither the medium nor the duration of culture (Day 3 versus Day 5 blastocyst transfer) had any effect on mean singleton birthweight.nnnWHAT IS KNOWN ALREADYnPrevious studies indicated that in vitro culture of human embryos may affect birthweight of live born singletons. Both the type of culture medium and the duration of culture may be implicated. However, these studies are small and report conflicting results.nnnSTUDY DESIGN, SIZE, DURATIONnA large retrospective analysis was performed including all singleton live births after transferring fresh Day 3 or Day 5 embryos. IVF and ICSI cycles performed between April 2004 and December 2009 at a tertiary care centre were included for analysis.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnA total of 2098 singleton live births resulting from singleton pregnancies were included for analysis. Two different sequential embryo culture media were concurrently used in an alternating way: Medicult (n = 1388) and Vitrolife (n = 710). Maternal age, maternal and paternal BMI, maternal parity, maternal smoking, main cause of infertility, cycle rank, stimulation protocol, method of fertilization (IVF or ICSI), time in culture and number of embryos transferred were taken into account. Embryo transfers were performed either on Day 3 (n = 1234) or on Day 5 (n = 864). Singleton birthweight was the primary outcome parameter. Gestational age and gender of the newborn were accounted for in the multiple regression analysis.nnnMAIN RESULTS AND THE ROLE OF CHANCEnNo significant differences in mean singleton birthweight were observed between the two culture media: Medicult 3222 g (±15 SE) and Vitrolife 3251 g (±21 SE) (P = 0.264). The mean singleton birthweight was not different between Day 3 embryo transfers (3219 ± 16 g) and Day 5 blastocyst transfers (3250 ± 19 g; P = 0.209). Multiple regression analysis controlling for potential maternal, paternal, treatment and newborn confounders confirmed the non-significant differences in mean singleton birthweight between the two culture media. Likewise, the adjusted mean singleton birthweight was not different according to the duration of in vitro culture (P = 0.521).nnnLIMITATIONS, REASONS FOR CAUTIONnThe conclusions are limited by its retrospective design; however, the two different sequential culture systems were used in an alternating way during the same time period. Pregnancy-associated factors possibly influencing birthweight (such as diabetes, hypertension, pre-eclampsia) were not included in the analysis.nnnWIDER IMPLICATIONS OF THE FINDINGSnThis large retrospective study does not support earlier concerns that both the type of culture medium and the duration of embryo culture influence singleton birthweight. However, a continuous surveillance of human embryo culture procedures (medium type, culture duration and other culture conditions) should remain a priority within assisted reproduction technology.nnnSTUDY FUNDING/COMPETING INTERESTSnNone.

Laterality in five-year-olds conceived by intracytoplasmic sperm injection, standard in vitro fertilisation and natural conception: a European study

Objectiveu2003 To assess laterality in a group of European children conceived with the help of assisted reproductive therapy, or naturally conceived.

Intracytoplasmic sperm injection — ICSI

For more than a decade in vitro fertilization (IVF) has been successful in the treatment of couples with long-standing infertility due to various aetiologies such as tubal disease, male-factor infertility, unexplained infertility and endometriosis. The usual fertilization rate in IVF for nonmale infertility cases is 60–70% of the inseminated cumulus-oocyte complexes and in andrological infertility it is only 20–30%. The lower the number of normally fertilized oocytes, the less chance there is of available embryos, so that patients may have no embryos to transfer. It has been the experience of all centres for reproductive medicine, including our own, that a certain number of couples with male-factor infertility cannot be helped by standard IVF treatment. After insemination with progressively motile spermatozoa the number of two-pronuclear oocytes was either zero or less than 5%. Furthermore, a sizeable number of couples cannot be accepted for IVF if the number of progressively motile spermatozoa in the ejaculate is below a certain threshold number such as 500 000. In the past five years, assisted fertilization procedures have been developed to circumvent the barriers that prevent sperm access to the ooplasma, namely the zona pellucida and the ooplasmic membrane. Pregnancies and births have been reported after partial zona dissection (PZD) and subzonal insemination (SUZI). The success rate of PZD and SUZI has remained moderate: the normal fertilization rate (two-pronuclear oocytes) has never exceeded 20–25% of the micromanipulated oocytes; only two-thirds of the patients have had embryo transfers of, usually, a low number of embryos, resulting in a reduced pregnancy and take-home baby rate.

Body composition and blood pressure in 6-year-old singletons born after pre-implantation genetic testing for monogenic and structural chromosomal aberrations: a matched cohort study

Abstract STUDY QUESTION Does Day 3 embryo biopsy for pre-implantation genetic testing for monogenic (PGT-M) and structural chromosomal aberrations (PGT-SR) affect body composition and blood pressure readings of 6-year-old singletons? SUMMARY ANSWER This study of 87 PGT-M and PGT-SR conceived singletons showed no differences in anthropometric measurements and blood pressure readings in comparison with a matched cohort of peers born after ICSI without embryo biopsy. WHAT IS KNOWN ALREADY While neonatal outcomes after PGT conception have been found comparable to those after ICSI without embryo biopsy, only a few studies have reported outcomes after PGT at older ages. Moreover, embryo biopsy is also applied in couples who opt for PGT-M and PGT-SR and hence are not necessarily infertile. Health parameters and in particular body composition data in this group of children are lacking. STUDY DESIGN, SIZE, DURATION This single-centre matched-pair cohort study evaluated body composition of 6-year-old children born after fresh blastocyst embryo transfer with or without embryo biopsy performed at Day 3 for the purpose of PGT-M and PGT-SR. For each child born after embryo biopsy, a singleton born after transfer of a fresh ICSI embryo at the blastocyst stage and reaching the age of 6 years between May 2011 and June 2017 was matched as closely as possible for gender, age, maternal educational level and birth order. PARTICIPANTS/MATERIALS, SETTING, METHODS Anthropometry (weight, height, BMI, skinfold thickness, waist and mid-upper arm circumference) and blood pressure readings in a longitudinally followed cohort of 87 singletons conceived by PGT-M and PGT-SR and a pairwise matched sample of 87 children conceived by ICSI are described. Results are adjusted for current, neonatal and parental characteristics. MAIN RESULTS AND THE ROLE OF CHANCE From the 124 eligible PGT-M and PGT-SR families, 110 could be reached of whom 23 refused and 87 (87/110 = 79%) participated. All anthropometric measurements, including z-scores of BMI, waist and mid-upper arm circumference, were comparable between the PGT-M and PGT-SR (−0.23; 0.27; 0.17, respectively) and ICSI (−0.29; 0.11; 0.11, respectively) groups (all P > 0.05). Furthermore, indices of peripheral (triceps) and central (subscapular) adiposity derived from skinfold thickness were comparable (PGT-M and PGT-SR: 14.7 mm; 11.6 mm and ICSI: 15.5 mm; 11.5 mm) as well as the percentage total body fat mass derived from these (PGT-M and PGT-SR: 13.7% and ICSI: 13.9%) (all P > 0.05). Z-scores for blood pressure were also comparable between the PGT and ICSI groups (all P > 0.05). Results did not change when adjusted for neonatal (birthweight, birth order), current (age) and parental (smoking during pregnancy, parental BMI) characteristics. Hospitalization rate and surgical intervention rate were not different for PGT-M and PGT-SR children compared to matched peers born after ICSI. LIMITATIONS, REASONS FOR CAUTION Although our study describes the largest cohort of singletons born after embryo biopsy worldwide, we were only able to detect moderate differences in anthropometrics and blood pressure with our sample size. WIDER IMPLICATIONS OF THE FINDINGS Although Day 3 embryo biopsy followed by blastocyst transfer is not associated with adverse outcomes regarding anthropometry and blood pressure, future studies should focus on outcomes in children born after trophectoderm biopsy and/or transfer of warmed embryos after vitrification. STUDY FUNDING/COMPETING INTEREST(s) This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts; all issued by the Vrije Universiteit Brussel (VUB). All co-authors, except M.B. declared no conflict of interest. M.B. has received consultancy fees from MSD, Serono Symposia and Merck. The Universitair Ziekenhuis Brussel (UZ Brussel) and the Centre for Medical Genetics have received several educational grants from IBSA, Ferring, Organon, Shering-Plough, Merck for establishing the database for follow-up research and organizing the data collection.

Outcome of Pregnancies After Intracytoplasmic Sperm Injection and the Effect of Sperm Origin and Quality of This Outcome

OBJECTIVEnTo 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.nnnDESIGNnRetrospective analysis.nnnSETTINGnA tertiary referral center for assisted reproduction.nnnPATIENT(S)nPregnant patients conceived after microinjection of ejaculated sperm (n=1,427), epididymal sperm (n=79), and testicular sperm (n=93).nnnINTERVENTION(S)nICSI, epididymal sperm aspiration, and testicular biopsy.nnnMAIN OUTCOME MEASURE(S)nStillbirth, prematurity, and early perinatal mortality.nnnRESULT(S)nThe 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 per thousand. 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.nnnCONCLUSION(S)nThe 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.