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Assessing risk of neurodevelopmental disorders after birth with oxytocin: a systematic review and meta-analysis

Published online by Cambridge University Press:  16 November 2018

Nicole N. Lønfeldt Open the ORCID record for Nicole N. Lønfeldt [Opens in a new window] ,
Frank C. Verhulst Open the ORCID record for Frank C. Verhulst [Opens in a new window] ,
Katrine Strandberg-Larsen Open the ORCID record for Katrine Strandberg-Larsen [Opens in a new window] ,
Kerstin J. Plessen Open the ORCID record for Kerstin J. Plessen [Opens in a new window]  and
Eli R. Lebowitz Open the ORCID record for Eli R. Lebowitz [Opens in a new window]
Nicole N. Lønfeldt*
Affiliation:
Child and Adolescent Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark Section for Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
Frank C. Verhulst
Affiliation:
Child and Adolescent Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands
Katrine Strandberg-Larsen
Affiliation:
Section for Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
Kerstin J. Plessen
Affiliation:
Child and Adolescent Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark Division Child Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland
Eli R. Lebowitz
Affiliation:
Yale Child Study Center, New Haven, Connecticut, USA
*
Author for correspondence: Nicole N. Lønfeldt, E-mail: nicole.nadine.loenfeldt@regionh.dk
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Abstract

Experts have raised concerns that oxytocin for labor induction and augmentation may have detrimental effects on the neurodevelopment of children. To investigate whether there is the reason for concern, we reviewed and evaluated the available evidence by searching databases with no language or date restrictions up to 9 September 2018. We included English-language studies reporting results on the association between perinatal oxytocin exposure and any cognitive impairment, psychiatric symptoms or disorders in childhood. We assessed the quality of studies using the Newcastle–Ottawa Quality Assessment Scales. Independent risk estimates were pooled using random-effects meta-analyses when at least two independent datasets provided data on the same symptom or disorder. Otherwise, we provided narrative summaries. Two studies examined cognitive impairment, one examined problem behavior, three examined attention-deficit/hyperactivity disorder (ADHD) and seven focused on autism spectrum disorders (ASD). We provided narrative summaries of the studies on cognitive impairment. For ADHD, the pooled risk estimate was 1.17; 95% confidence interval (CI) 0.77–1.78, based on a pooled sample size of 5 47 278 offspring. For ASD, the pooled risk estimate was 1.10; 95% CI 1.04–1.17, based on 8 87 470 offspring. Conclusions that perinatal oxytocin increases the risks of neurodevelopmental problems are premature. Observational studies of low to high quality comprise the evidence-base, and confounding, especially by the genetic or environmental vulnerability, remains an issue. Current evidence is insufficient to justify modifying obstetric guidelines for the use of oxytocin, which state that it should only be used when clinically indicated.

Keywords

ADHDadolescentsASDchildrenoxytocinperinatal risk factors

Information

Type
Review Article
Information
Psychological Medicine , Volume 49 , Issue 6 , April 2019 , pp. 881 - 890
Copyright
Copyright © Cambridge University Press 2018 

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References

Achenbach, TM (1991) Manual for the Child Behavior Checklist/4-18 and 1991 Profile. Burlington: Department of Psychiatry, University of Vermont.Google Scholar
Al-Ayadhi, LY (2005) Altered oxytocin and vasopressin levels in autistic children in Central Saudi Arabia. Neurosciences 10, 47–50.Google Scholar
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th Edn. DSM 5. Arlington, VA: American Psychiatric Association.Google Scholar
Bales, KL and Carter, CS (2003) Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (Microtus ochrogaster). Hormones and Behavior, Special Issue on Aggressive and Violent Behavior 44, 178–184.Google Scholar
Bell, AF, Erickson, EN and Carter, CS (2014) Beyond labor: the role of natural and synthetic oxytocin in the transition to motherhood. Journal of Midwifery and Women's Health 59, 35–42.Google Scholar
Buckley, SJ (2015) Executive summary of hormonal physiology of childbearing: evidence and implications for women, babies, and maternity care. Journal of Perinatal Education 24, 145–153.Google Scholar
Cochran, DM, Fallon, D, Hill, MB and Frazier, JA (2013) The role of oxytocin in psychiatric disorders: a review of biological and therapeutic research findings. [Review]. Harvard Review of Psychiatry 21, 219–247.Google Scholar
Dadds, MR, Moul, C, Cauchi, A, Dobson-Stone, C, Hawes, DJ, Brennan, J and Ebstein, RE (2014) Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. Development and Psychopathology 26, 33–40.Google Scholar
Declercq, ER, Sakala, C, Corry, MP and Applebaum, S (2007) Listening to mothers II: report of the second national U.S. survey of women's childbearing experiences. Journal of Perinatal Education 16, 9–14.Google Scholar
Freedman, D, Brown, AS, Shen, L and Schaefer, CA (2015) Perinatal oxytocin increases the risk of offspring bipolar disorder and childhood cognitive impairment. Journal of Affective Disorders 173, 65–72.Google Scholar
Gale, S, Ozonoff, S and Lainhart, J (2003) Brief report: pitocin induction in autistic and nonautistic individuals. Journal of Autism and Developmental Disorders 33, 205–208.Google Scholar
Gialloreti, LE, Benvenuto, A, Benassi, F and Curatolo, P (2014) Are caesarean sections, induced labor and oxytocin regulation linked to autism spectrum disorders? Medical Hypotheses 82, 713–718.Google Scholar
Goffinet, F, Dreyfus, M, Carbonne, B, Magnin, G and Cabrol, D (2003) [Survey of the practice of cervical ripening and labor induction in France]. Journal de Gynécologie Obstétrique et Biologie de la Reproduction 32, 638–646.Google Scholar
Gonzalez-Valenzuela, MJ, García-Fortea, P, Delgado-Ríos, M, Cazorla-Granados, O, Blasco-Alonso, M and Gonzalez-Mesa, ES (2014) Effects of oxytocin used during delivery on development: a retrospective cohort study. Journal of Clinical and Experimental Neuropsychology 36, 680–690.Google Scholar
Gregory, SG, Connelly, JJ, Towers, AJ, Johnson, J, Biscocho, D, Markunas, CA, Lintas, C, Abramson, RK, Wright, HH, Ellis, P, Langford, CF, Worley, G, Delong, GR, Murphy, SK, Cuccaro, ML, Persico, A and Pericak-Vance, MA (2009) Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Medicine 7, 62.Google Scholar
Gregory, SG, Anthopolos, R, Osgood, CE, Grotegut, CA and Miranda, ML (2013) Association of autism with induced or augmented childbirth in North Carolina birth record (1990–1998) and education research (1997–2007) databases. JAMA Pediatrics 167, 959–966.Google Scholar
Guastella, AJ, Cooper, MN, White, CRH, White, MK, Pennell, CE and Whitehouse, AJO (2018) Does perinatal exposure to exogenous oxytocin influence child behavioural problems and autistic-like behaviours to 20 years of age? Journal of Child Psychology and Psychiatry. doi: https://doi.org/10.1111/jcpp.12924.Google Scholar
Hartling, L, Hamm, M, Milne, A, Vandermeer, B, Santaguida, PL, Ansari, M, Tsertsvadze, A, Hempel, S, Shekelle, P and Dryden, DM (2012) Validity and Inter-Rater Reliability Testing of Quality Assessment Instruments. Rockville: Agency for Healthcare Research and Quality.Google Scholar
Henriksen, L, Wu, CS, Secher, NJ, Obel, C and Juhl, M (2015) Medical augmentation of labor and the risk of ADHD in offspring: a population-based study. Pediatrics 135, e672–e677.Google Scholar
Herrera, C, Bakian, A, Fraser, A, Varner, MW, Esplin, S and Clark, EAS (2017) 162: exogenous oxytocin for labor induction or augmentation and autism spectrum disorder. American Journal of Obstetrics & Gynecology 216, 109.Google Scholar
Higgins, JPT, Thompson, SG, Deeks, JJ and Altman, DG (2003) Measuring inconsistency in meta-analyses. British Medical Journal 327, 557–560.Google Scholar
Hollander, E, Cartwright, C, Wong, CM, DeCaria, CM, DelGiudice-Asch, G, Buchsbaum, MS and Aronowitz, BR (1998) A dimensional approach to the autism spectrum. CNS Spectrums 3, 22–39.Google Scholar
Jia, R, Tai, F, An, S, Broders, H and Sun, R (2008 a) Neonatal manipulation of oxytocin influences the partner preference in mandarin voles (Microtus mandarinus). Neuropeptides 42, 525–533.Google Scholar
Jia, R, Tai, FD, An, SC, Broders, H, Ding, XL, Kong, Q, Zhao, L and Zhang, H (2008 b) Effects of neonatal oxytocin treatment on aggression and neural activities in mandarin voles. Physiology & Behavior 95, 56–62.Google Scholar
Kalyoncu, T, Özbaran, B, Köse, S and Onay, H (2017) Variation in the oxytocin receptor gene is associated with social cognition and ADHD. Journal of Attention Disorders. doi: https://doi.org/10.1177/1087054717706757.Google Scholar
Kurth, L and Haussmann, R (2011) Perinatal pitocin as an early ADHD biomarker: neurodevelopmental risk? Journal of Attention Disorders 15, 423–431.Google Scholar
Lain, SJ (2012) Quality of data in perinatal population health databases: a systematic review. Medical Care 50, e7–20.Google Scholar
Landgraf, R and Neumann, ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Frontiers in Neuroendocrinology 25, 150–176.Google Scholar
Lefevre, A and Sirigu, A (2016) The two fold role of oxytocin in social developmental disorders: a cause and a remedy? Neuroscience and Biobehavioral Reviews 63, 168–176.Google Scholar
Loparo, D and Waldman, ID (2015) The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Molecular Psychiatry 20, 640–646.Google Scholar
Miller, S (2016) Beyond too little, too late and too much, too soon: a pathway towards evidence-based, respectful maternity care worldwide. Lancet 388, 2176–2192.Google Scholar
Oberg, AS, D'Onofrio, BM, Rickert, ME, Hernandez-Diaz, S, Ecker, JL, Almqvist, C, Larsson, H, Lichtenstein, P and Bateman, BT (2016) Association of labor induction with offspring risk of autism spectrum disorders. JAMA Pediatrics 170, e160965.Google Scholar
Park, J, Willmott, M, Vetuz, G, Toye, C, Kirley, A, Hawi, Z, Brookes, KJ, Gill, M and Kent, L (2010) Evidence that genetic variation in the oxytocin receptor (OXTR) gene influences social cognition in ADHD. Progress in Neuro-Psychopharmacology and Biological Psychiatry 34, 697–702.Google Scholar
Patsopoulos, NA, Evangelou, E and Ioannidis, JP (2008) Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation. International Journal of Epidemiology 37, 1148–1157.Google Scholar
Plothe, C (2009) The perinatal application of oxytocin and its possible influence on the human psyche. International Journal of Prenatal and Perinatal Psychology and Medicine 21, 181–198.Google Scholar
Sacrez, R, Berland, H, Gandar, R, Irrmann, M, Schleider, G and Francfort, JJ (1969) Study of the effects of synthetic oxytocin perfused intravenously in obstetrics to induce labor on the physical state and psychomotor development of the newborn. Etude des incidences de l'ocytocine synthetique employee en obstetrique en perfusion intra-veineuse pour le ceclenchement du travail sur l'etat physique du nouveau-ne et sur son developpement psychomoteur. Annales de Pédiatrie 16, 27–33.Google Scholar
Sasaki, T, Hashimoto, K, Oda, Y, Ishima, T, Kurata, T, Takahashi, J, Kamata, Y, Kimura, H, Niitsu, T, Komatsu, H, Ishikawa, M, Hasegawa, T, Shiina, A, Hashimoto, T, Kanahara, N, Shiraishi, T and Iyo, M (2015) Decreased levels of serum oxytocin in pediatric patients with attention deficit/hyperactivity disorder. Psychiatry Research 228, 746–751.Google Scholar
Selin, L (2009) Use and abuse of oxytocin for augmentation of labor. Acta Obstetricia et Gynecologica Scandinavica 88, 1352–1357.Google Scholar
Shadish, WR and Haddock, CK (2009) Combining estimates of effect size. In Cooper, H, Hedges, L and Valetine, J (eds), The Handbook of Research Synthesis and Meta-Analysis. New York: Russell Sage Foundation, pp. 257–278.Google Scholar
Silva, D, Colvin, L, Hagemann, E and Bower, C (2014) Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder. Pediatrics 133, E14–E22.Google Scholar
Smallwood, M, Sareen, A, Baker, E, Hannusch, R, Kwessi, E and Williams, T (2016) Increased risk of autism development in children whose mothers experienced birth complications or received labor and delivery drugs. ASN Neuro 8, 1–7.Google Scholar
Stang, A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European Journal Epidemiology 25, 603–605.Google Scholar
Stokholm, L, Juhl, M, Lønfeldt, NN, Mikkelsen, SH, Obel, C and Strandberg-Larsen, K (2018) Obstetric synthetic oxytocin use and subsequent hyperactivity/inattention problems in Danish children. Acta Obstetricia et Gynecologica Scandinavica 97, 880–889.Google Scholar
Stroup, DF, Berlin, JA, Morton, SC, Olkin, I, Williamson, GD, Rennie, D, Moher, D, Becker, BJ, Sipe, TA, Thacker, SB and (MOOSE) Group, for the M.O.O.S. in E. (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Journal of the American Medical Association 283, 2008–2012.Google Scholar
Symons, MJ and Moore, DT (2002) Hazard rate ratio and prospective epidemiological studies. Journal of Clinical Epidemiology 55, 893–899.Google Scholar
The Cochrane Collaboration (2014) Review Manager. Copenhagen: The Nordic Cochrane Centre.Google Scholar
Wahl, RUR (2004) Could oxytocin administration during labor contribute to autism and related behavioral disorders? – A look at the literature. Medical Hypotheses 63, 456–460.Google Scholar
Weinstock, M (2005) The potential influence of maternal stress hormones on development and mental health of the offspring. Brain, Behavior, and Immunity 19, 296–308.Google Scholar
Weisman, O, Agerbo, E, Carter, CS, Harris, JC, Uldbjerg, N, Henriksen, TB, Thygesen, M, Mortensen, PB, Leckman, JF and Dalsgaard, S (2015) Oxytocin-augmented labor and risk for autism in males. Behavioural Brain Research 284, 207–212.Google Scholar
Wells, GA, Shea, B, O'Connell, D, Peterson, J, Welch, V, Losos, M and Tugwell, P (2010) The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Available at http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. (Accessed 17 June 2017).Google Scholar
World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines 1. Geneva: World Health Organization.Google Scholar
World Health Organization (2011) WHO Recommendations for Induction of Labour. Geneva: World Health Organization.Google Scholar
World Health Organization (2014) WHO Recommendations for Augmentation of Labour. Geneva: World Health Organization.Google Scholar
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