Download PDF
Am J Perinatol 2019; 36(09): 949-954
DOI: 10.1055/s-0038-1675159
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Infertility Treatments and Long-Term Neurologic Morbidity of the Offspring

Shai Levin
1   Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
,
Eyal Sheiner
2   Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
,
Tamar Wainstock
3   Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
,
Asnat Walfisch
2   Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
,
Idit Segal
4   Department of Medical Affairs, Ministry of Health, Jerusalem, Israel
,
Daniella Landau
5   Department of Neonatology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
,
Ruslan Sergienko
3   Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
,
Eliahu Levitas
2   Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
,
Avi Harlev
2   Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
› Author Affiliations
Further Information

Publication History

27 January 2018

05 September 2018

Publication Date:
16 November 2018 (online)

Also available at
    Permissions and Reprints

Abstract

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.

Keywords

long-term pediatric neurologic morbidity - fertility treatments - in vitro fertilization - ovulation induction

Note

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.


Supplementary Material

 

  • References

  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 17 Mains L, Zimmerman M, Blaine J. , et al. Achievement test performance in children conceived by IVF. Hum Reprod 2010; 25 (10) 2605-2611
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 21 Laprise SL. Implications of epigenetics and genomic imprinting in assisted reproductive technologies. Mol Reprod Dev 2009; 76 (11) 1006-1018
    CrossrefPubMedGoogle Scholar
  • 22 Israel Central Bureau of Statistics. Annual data 2017. 2017
    PubMed
  • 23 Wang ZJ, Liu JF. The molecular basis of insomnia: implication for therapeutic approaches. Drug Dev Res 2016; 77 (08) 427-436
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 31 Persson B, Hanson U. Neonatal morbidities in gestational diabetes mellitus. Diabetes Care 1998; 21 (Suppl. 02) B79-B84
    CrossrefPubMedGoogle Scholar