Assisted Reproduction and Child Neurodevelopment at age 5

Transcription

1 Protokol til Bedre Sundhed for Mor og Barn m.h.p. anvendelse af datamateriale BSMB J. nr Assisted Reproduction and Child Neurodevelopment at age 5 Bjørn Bay, M.D Supervisors Ulrik Schiøler Kesmodel, MD, PhD 1 Erik Lykke Mortensen, MSc (Psych), Adjunct Professor 2 1 School of Public Health, Department of Epidemiology, Aarhus University, Denmark and The Fertility Clinic, Department. of Gynecology and Obstetrics, Aarhus University Hospital, Skejby. 2 Department of Public Health, University of Copenhagen, Denmark.

2 Objective The project is a part of a PhD study at Aarhus University. The aim of this project is to add significant knowledge on the neuropsychological outcomes of children conceived after use of assisted reproductive techniques (ART). The objectives of this project are to investigate the effect of ART on child IQ, attention, executive functions and behavior. Background Infertility, usually defined as a failure to achieve a clinically recognized pregnancy after more than 12 months of unprotected intercourse, affects about 10-20% in many industrialized countries (1), and an increasing number of infertile couples seek medical treatment (2). In vitro fertilization (IVF) and intracytoplasmatic semen injection (ICSI) are well-recognized treatment techniques, helping more than 85 % of infertile couples to conceive within a year (3). Since the first child was conceived after IVF in the UK in 1978 more than 1 million babies have been born after IVF treatment (4, 5). In developed countries, ART contribute to more than 1% of births (5) in some countries (e.g. Denmark) up to 9% (6). Over the last few years, several follow up studies have been published on potentially adverse pregnancy outcomes including miscarriage, malformations, preterm delivery, growth restriction, and stillbirth (7). Singletons born after ART have a higher rate of adverse pregnancy outcome; IVF in general are associated with a 50% increased risk of malformations (8) and regarding specific birth defects, ovarian stimulation has been associated with oral-facial clefts and possibly other malformations, whereas ICSI has been related to urogenital malformation among boys (8). However, few studies have been performed on the neuropsychological development of children born after ART. A few studies with limited sample size have been performed (9-11). Although most studies found no major psychomotor developmental delays in children born after IVF (5) and the study findings for ICSI children are equivalent (12-15), many studies have methodological limitations (e.g. small sample studies, selection bias, high rate of dropouts, lack of sufficient confounder control)(12, 16). Any risk for the children conceived after ART could arise because of the medical ovarian stimulation, because of the altered selection of the fertilizing spermatozoa especially in the case of ICSI where a single spermatozoa is introduced into the oocyte by micro insemination or because e.g. men with low sperm quality are more likely to have chromosomal abnormalities that they may pass on to the offspring (17). ICSI is the more invasive and selective technique, and there are plausible biological reasons such as a higher rate of chromosomal anomalies why ICSI children may be at increased risk for delayed neurodevelopment (18, 19). The risk increase could also be an effect of the characteristics of the mother undergoing ART, or the father, whose semen is used for the fertilization (homo or heterolog donation). Children born after ART are more often high birth order which alone raises the risk of adverse outcomes. When restricted to singletons, children born after ART also have a higher rate of adverse pregnancy outcomes such as preterm delivery and reduced 1

3 fetal growth, which are risk factors for neurodevelopment delays (5). Still other factors contribute to the cognitive development of ART children, e.g. gender, parity, parental education (13), maternal intelligence and maternal age (20). When conducting a large-scale epidemiological study of the possibly differences in neurodevelopment between ART and spontaneously conceived children, all these factors must be taken into account and controlled for in the analyses. However, none of the previous studies have adjusted for all the most important predictors and risk factors of child neuropsychological development. Hypotheses IVF and ICSI treatment is associated with lower offspring IQ at age 5. IVF and ICSI treatment is associated with attention deficits in the offspring at age 5. IVF and ICSI treatment is associated with executive functions deficits in the offspring at age 5. IVF and ICSI treatment is associated with behavior disturbances in the offspring at age 5. Methods Design Follow-up study. Population The population for this study are the 1628 mother-child pairs who participated in the Lifestyle During Pregnancy Study (LDPS) (21), to which they had been recruited from the Danish National Birth Cohort (DNBC) (22), a study containing pre- and postnatal information on 101,042 women and their offspring from From two prenatal maternal telephone interviews in the DNBC we can extract data regarding the conception, pregnancy, maternal health, use of medicine, socioeconomic status, and life style factors (e.g. alcohol, smoking). In the LDPS the participants were originally recruited as a stratified sample across levels of alcohol intake during pregnancy. Exclusion criteria for the Lifestyle Study were the child s inability to speak Danish, impaired hearing or vision to the extent that the test session could not be performed, multiple pregnancies, and congenital diseases likely to cause mental retardation (e.g. Downs syndrome). Data collection Procedure Data collection of child neuropsychological development took place in the period November June The selected women were contacted by letter approximately 8-12 weeks before the child turned five years of age. When the child was between 5 years, 0 months and 5 years, 4 months of age, a three-hour examination was carried out at one of four test sites in Aalborg, Aarhus, Odense and Copenhagen. The assessment comprised a 2

4 neuropsychological test battery and a physical examination including a test of motor function (see below). Trained psychologists blinded to exposure status administered the tests. A project developed questionnaire and two standardized questionnaires were mailed and filled in by the mother and a person from the child s day care (standardized questionnaires only) (21). Test procedures were standardized into detail and interrater studies were carried out on a regular basis to maximize interrater reliability. Test sessions in each of the four locations were evenly distributed between the testing personnel in order to reduce tester bias (21). The scores from the neuropsychological test battery are cleaned and ready for further analyses in datasets. Exposure information Information on IVF and ICSI treatment in the index pregnancy will be obtained from the DNBC and from the IVF registry administered by the Danish National Board of Health. Validation of the information will be performed by checking the medical records of persons with any information on potential ART treatment. Outcome measures The entire test battery conducted in the LDPS comprises measures of global cognitive functioning as well as specific physical and neurological functions and domains. In this PhD project, we use information on: 1. Global Intellectual Functioning Measured by verbal and performance IQ on the Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R) (23). A standardized and validated test with psychometric properties proven stable (24) and for this reason among the most widely used measures of cognitive functioning and development. 2. Attention Measured by the Teach-5 (21), which is a test of different aspects of attention (sustained, selective, spatial, control/inhibition) in different modalities (visual/auditory). 3. Executive functions Measured by Behaviour Rating Inventory of Executive Functions (BRIEF) (25). A questionnaire to parents and day care with subscales of executive functions (emotional control, working memory, organization of material etc.) 4. Behavior Measured by the Strengths and Difficulties Questionnaire (SDQ) (26) - A behavioural screening instrument consisting of a parent and a teacher form each containing 25 questions asking about different positive as well as negative aspects of the child s behaviour. 3

5 Analytic approach All statistical analyses will be conducted with Stata 11 (StataCorp LP, College Station, Texas) and weighted by sampling probabilities from the DNBC. From the DNBC, the lifestyle study and the Danish National Birth register, we will extract data to form a set of a priori defined possible confounding variables that could affect their performance on the outcome measures. These include maternal age, BMI, marital status, prenatal alcohol and tobacco use, parity, maternal IQ and parental education, index of family/home environment as well as child age at testing, sex, child health, vision, and hearing. Birth weight and gestational age are considered as potential mediators and will not be included in the main analyses. We will conduct appropriate multivariate analyses, and if one or more data are missing we will impute the missing values by multiple imputation strategy as well as do complete case analyses. The analyses will be conducted on a model of data analysis developed for the LDPS with adjustment for core or all potential confounding variables. We will do interaction analyses and stratified analyses of appropriate variables. Power calculations To calculate the difference we would expect to find with statistical significance between the children conceived after different types of assisted reproduction techniques we initially defined the number of participants in each groups based on the information from the DNBC (Table 1). Then, we calculated the difference we would expect to find with at power estimate at 80% (Table 2). Graphic presentation of the results from the calculation is in appendix 1. The minimum difference with a clinically significance is for the four outcome measures estimated to be 0.5 SD. Previous scientific experience As a scientific assistant at the School of Public Health, Aarhus University, I have worked 8 months as a part of the research group in the LDPS. Beside earlier work, I have published one paper and have two more closely related to the study 1 in the planned PhD project ready for submission. Thru the work with the LDPS group I have become familiar with the outcomes and the models for confounder adjustments an experience I will be able to benefit from in study 1 in this PhD project. Perspectives With increasing use of ART in the treatment of infertile couples, investigations regarding the safety are continuously required. This study has the potential to add significantly to the current knowledge of the neuropsychological outcomes of ART children. If a significant difference is discovered, this work could form the basis for better information to the infertile couples. In contrast, if no differences are discovered, it could be reassuring for the future infertile couples naturally concerned for the development of their offspring. 4

6 Publication plan The plan is to write 2 scientific papers: Does assisted reproduction affect offspring IQ and attention a cohort study. Does assisted reproduction affect child executive functions and behavior a cohort study. 5

7 References 1. Juul S, Karmaus W, Olsen J, Fletcher T, Bolumar F, Fig -Talamanca I, et al. Regional differences in waiting time to pregnancy: Pregnancy-based surveys from Denmark, France, Germany, Italy and Sweden. Human Reproduction. 1999;14(5): Olsen J, Kuppers-Chinnow M, Spinelli A. Seeking medical help for subfecundity: A study based upon surveys in five European countries. Fertility and Sterility. 1996;66(1): Steel AJ, Sutcliffe A. Long-term health implications for children conceived by IVF/ICSI. Hum Fertil (Camb) Mar;12(1): Basatemur E, Sutcliffe A. Follow-up of children born after ART. Placenta Oct;29 Suppl B: Sutcliffe AG, Ludwig M. Outcome of assisted reproduction. Lancet Jul 28;370(9584): DFS. Year Report. Danish Fertility Society Williams C, Sutcliffe A. Infant outcomes of assisted reproduction. Early Hum Dev Nov;85(11): Ericson A, K ll n B. Congenital malformations in infants born after IVF: A population-based study. Human Reproduction. 2001;16(3): Ludwig A, Katalinic A, Thyen U, Sutcliffe AG, Diedrich K, Ludwig M. Neuromotor development and mental health at 5.5 years of age of singletons born at term after intracytoplasmatic sperm injection ICSI: results of a prospective controlled single-blinded study in Germany. Fertil Steril Jan;91(1): Olivennes F, Fanchin R, L d e N, Righini C, Kadoch IJ, Frydman R. Perinatal outcome and developmental studies on children born after IVF. Human Reproduction Update. 2002;8(2): Schieve LA, Rasmussen SA, Buck GM, Schendel DE, Reynolds MA, Wright VC. Are children born after assisted reproductive technology at increased risk for adverse health outcomes? Obstetrics and Gynecology. 2004;103(6): Goldbeck L, Gagsteiger F, Mindermann I, Strobele S, Izat Y. Cognitive development of singletons conceived by intracytoplasmic sperm injection or in vitro fertilization at age 5 and 10 years. J Pediatr Psychol Aug;34(7): Leunens L, Celestin-Westreich S, Bonduelle M, Liebaers I, Ponjaert-Kristoffersen I. Cognitive and motor development of 8-year-old children born after ICSI compared to spontaneously conceived children. Hum Reprod Nov;21(11): Leunens L, Celestin-Westreich S, Bonduelle M, Liebaers I, Ponjaert-Kristoffersen I. Follow-up of cognitive and motor development of 10-year-old singleton children born after ICSI compared with spontaneously conceived children. Hum Reprod Jan;23(1): Middelburg KJ, Heineman MJ, Bos AF, Hadders-Algra M. Neuromotor, cognitive, language and behavioural outcome in children born following IVF or ICSI-a systematic review. Hum Reprod Update May-Jun;14(3): Zhu JL, Basso O, Obel C, Hvidtjorn D, Olsen J. Infertility, infertility treatment and psychomotor development: the Danish National Birth Cohort. Paediatr Perinat Epidemiol Mar;23(2): Magli MC, Gianaroli L, Ferraretti AP, Gordts S, Fredericks V, Crippa A. Paternal contribution to aneuploidy in preimplantation embryos. Reproductive BioMedicine Online. 2009;18(4): Bonduelle M, Ponjaert I, Van Steirteghem A, Derde MP, Devroey P, Liebaers I. Developmental outcome at 2 years of age for children born after ICSI compared with children born after IVF. Human Reproduction. 2003;18(2): Leslie GI, Gibson FL, McMahon C, Cohen J, Saunders DM, Tennant C. Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age. Human Reproduction. 2003;18(10): Ponjaert-Kristoffersen I, Bonduelle M, Barnes J, Nekkebroeck J, Loft A, Wennerholm UB, et al. International collaborative study of intracytoplasmic sperm injection-conceived, in vitro fertilization-conceived, and naturally conceived 5-year-old child outcomes: Cognitive and motor assessments. Pediatrics. 2005;115(3). 6

8 21. Kesmodel US, Underbjerg M, Kilburn TR, Bakketeig L, Mortensen EL, Landro NI, et al. Lifestyle during pregnancy: Neurodevelopmental effects at 5 years of age. The design and implementation of a prospective follow-up study. Scand J Public Health Jan Olsen J, Melbye M, Olsen SF, Sørensen TIA, Aaby P, Andersen AMN, et al. The Danish National Birth Cohort - Its background, structure and aim. Scandinavian Journal of Public Health. 2001;29(4): Wechsler D. Manual for the Wechsler Preschool and Primary Scale of Intelligence -Revised. Sideup, Kent The Psychological Coorporation Sattler. Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R). Assessment of Children Cognitive Applications: Publisher, Inc., 2001; Ch.11; Sherman EMS, Brooks BL. Behavior rating inventory of executive function - Preschool version (BRIEF-P): Test review and clinical guidelines for use. Child Neuropsychology. 2010;16(5): Goodman R. The strengths and difficulties questionnaire: A research note. Journal of Child Psychology and Psychiatry and Allied Disciplines. 1997;38(5):

9 Appendix 1: Power calculation tables Table 1. Number of participants Outcome Measure Referencegroup Insemination IVF/ICSI ART WPPSI-R Teach BRIEF parents BRIEF teachers SDQ N/A N/A N/A N/A Table 2. Difference in scores with a power of 80% Outcome Measure 1 Insemination IVF/ICSI ART 2 Power Estimate 0.8 Power Estimate 0.8 Power Estimate 0.8 IQ, SD = 15 points IQ Attention, SD = 1 Teach Executive functions, SD = 10 BRIEF parents BRIEF teachers Behavior SDQ global score N/A 3 N/A 3 N/A 3 1. Described in differences from the reference group (No fertility treatment) 2. Participants answered yes to any kind of assisted reproduction 3. Not yet analyzed. 1

10 Appendix 2: Power calculation results graphically 1

11 2