Infertility Treatments and Long-Term Neurologic Morbidity of the Offspring
27 January 2018
05 September 2018
16 November 2018 (eFirst)
Objective To determine the risk of long-term neurologic morbidity among children (up to 18 years) born following in vitro fertilization (IVF) or ovulation induction (OI) treatments as compared with spontaneously conceived.
Study Design A population-based cohort analysis was performed, including data from the perinatal computerized database on all singleton infants born at the Soroka University Medical Center (SUMC) between the years 1991 and 2014. This perinatal database was linked and cross-matched with the SUMC computerized dataset of all pediatric hospitalizations.
Results Neurologic morbidity was significantly more common in IVF (3.7%) and OI (4.1%) offspring as compared with those following spontaneous pregnancies (3.1%; p = 0.017). In particular, attention deficit/hyperactivity disorders and headaches were more common in the OI group and sleep disorders in the IVF group, whereas autism and cerebral palsy were comparable between the groups. In the Weibull multivariable analysis, while controlling for maternal age, preterm delivery, birthweight centile, maternal diabetes, and hypertensive disorders, IVF (adjusted hazard ratio [HR]: 1.40; 95% confidence interval [CI]: 1.14–1.71; p = 0.001), but not OI (adjusted HR: 1.17' 95% CI: 0.92–1.48; p = 0.196), was noted as an independent risk factor for long-term pediatric neurologic morbidity.
Conclusion IVF offspring appear to be at an increased risk of long-term neurologic morbidity up to 18 years of age.
Keywordslong-term pediatric neurologic morbidity - fertility treatments - in vitro fertilization - ovulation induction
This study was conducted as part of the MD requirements for graduation from the Medical School of the Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.
- 1 Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med 2012; 9 (12) e1001356
- 2 Thoma ME, McLain AC, Louis JF. , et al. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril 2013; 99 (05) 1324-1331
- 3 Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2014. Natl Vital Stat Rep 2015; 64 (12) 1-64
- 4 Calhaz-Jorge C, de Geyter C, Kupka MS. , et al; European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. Hum Reprod 2016; 31 (08) 1638-1652
- 5 Youssef MA, van Wely M, Al-Inany H. , et al. A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial. Hum Reprod 2017; 32 (01) 112-118
- 6 Zarinara A, Zeraati H, Kamali K, Mohammad K, Shahnazari P, Akhondi MM. Models predicting success of infertility treatment: a systematic review. J Reprod Infertil 2016; 17 (02) 68-81
- 7 Wen J, Jiang J, Ding C. , et al. Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis. Fertil Steril 2012; 97 (06) 1331-1337
- 8 Klemetti R, Gissler M, Sevón T, Koivurova S, Ritvanen A, Hemminki E. Children born after assisted fertilization have an increased rate of major congenital anomalies. Fertil Steril 2005; 84 (05) 1300-1307
- 9 Silberstein T, Levy A, Harlev A, Saphier O, Sheiner E. Perinatal outcome of pregnancies following in vitro fertilization and ovulation induction. J Matern Fetal Neonatal Med 2014; 27 (13) 1316-1319
- 10 Ludwig AK, Sutcliffe AG, Diedrich K, Ludwig M. Post-neonatal health and development of children born after assisted reproduction: a systematic review of controlled studies. Eur J Obstet Gynecol Reprod Biol 2006; 127 (01) 3-25
- 11 Wainstock T, Walfisch A, Shoham-Vardi I. , et al. Fertility treatments and pediatric neoplasms of the offspring: results of a population-based cohort with a median follow-up of 10 years. Am J Obstet Gynecol 2017; 216 (03) 314.e1-314.e14
- 12 Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet 2002; 359 (9305): 461-465
- 13 Henningsen AK, Pinborg A, Lidegaard Ø, Vestergaard C, Forman JL, Andersen AN. Perinatal outcome of singleton siblings born after assisted reproductive technology and spontaneous conception: Danish national sibling-cohort study. Fertil Steril 2011; 95 (03) 959-963
- 14 Okby R, Druyan Y, Sonenklar M, Aricha-Tamir B, Sacks KN, Sheiner E. Fertility treatment as a risk factor for maternal request of cesarean delivery in twin pregnancies. Arch Gynecol Obstet 2016; 294 (06) 1183-1187
- 15 Middelburg KJ, Heineman MJ, Bos AF, Pereboom M, Fidler V, Hadders-Algra M. The Groningen ART cohort study: ovarian hyperstimulation and the in vitro procedure do not affect neurological outcome in infancy. Hum Reprod 2009; 24 (12) 3119-3126
- 16 Schendelaar P, Middelburg KJ, Bos AF, Heineman MJ, Jongbloed-Pereboom M, Hadders-Algra M. The Groningen ART cohort study: the effects of ovarian hyperstimulation and the IVF laboratory procedures on neurological condition at 2 years. Hum Reprod 2011; 26 (03) 703-712
- 17 Mains L, Zimmerman M, Blaine J. , et al. Achievement test performance in children conceived by IVF. Hum Reprod 2010; 25 (10) 2605-2611
- 18 Hvidtjørn D, Schieve L, Schendel D, Jacobsson B, Svaerke C, Thorsen P. Cerebral palsy, autism spectrum disorders, and developmental delay in children born after assisted conception: a systematic review and meta-analysis. Arch Pediatr Adolesc Med 2009; 163 (01) 72-83
- 19 Knoester M, Vandenbroucke JP, Helmerhorst FM, van der Westerlaken LA, Walther FJ, Veen S. Matched follow-up study of 5-8 year old ICSI-singletons: comparison of their neuromotor development to IVF and naturally conceived singletons. Hum Reprod 2007; 22 (06) 1638-1646
- 20 Katari S, Turan N, Bibikova M. , et al. DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum Mol Genet 2009; 18 (20) 3769-3778
- 21 Laprise SL. Implications of epigenetics and genomic imprinting in assisted reproductive technologies. Mol Reprod Dev 2009; 76 (11) 1006-1018
- 22 Israel Central Bureau of Statistics. Annual data 2017. 2017
- 23 Wang ZJ, Liu JF. The molecular basis of insomnia: implication for therapeutic approaches. Drug Dev Res 2016; 77 (08) 427-436
- 24 Garcia-Martínez I, Sánchez-Mora C, Pagerols M. , et al. Preliminary evidence for association of genetic variants in pri-miR-34b/c and abnormal miR-34c expression with attention deficit and hyperactivity disorder. Transl Psychiatry 2016; 6 (08) e879
- 25 Kim-Ha J, Kim YJ. Age-related epigenetic regulation in the brain and its role in neuronal diseases. BMB Rep 2016; 49 (12) 671-680
- 26 Walton E, Pingault JB, Cecil CA. , et al. Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study. Mol Psychiatry 2017; 22 (02) 250-256
- 27 Winsvold BS, Palta P, Eising E. , et al. International Headache Genetics Consortium. Epigenetic DNA methylation changes associated with headache chronification: a retrospective case-control study. Cephalalgia 2018; 38 (02) 312-322
- 28 Dunson DB, Colombo B, Baird DD. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002; 17 (05) 1399-1403
- 29 Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M. , et al. Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk. Pediatrics 2008; 121 (02) e223-e232
- 30 Cnattingius S, Forman MR, Berendes HW, Isotalo L. Delayed childbearing and risk of adverse perinatal outcome. A population-based study. JAMA 1992; 268 (07) 886-890
- 31 Persson B, Hanson U. Neonatal morbidities in gestational diabetes mellitus. Diabetes Care 1998; 21 (Suppl. 02) B79-B84