The etiology of autism is unknown, although perinatal and neonatal exposures have been the focus of epidemiologic research for over 40 years.
To provide the first review and meta-analysis of the association between perinatal and neonatal factors and autism risk.
PubMed, Embase, and PsycInfo databases were searched for studies that examined the association between perinatal and neonatal factors and autism through March 2007. Forty studies were eligible for the meta-analysis. For each exposure, a summary effect estimate was calculated using a random-effects model. Heterogeneity in effect estimates across studies was examined, and, if found, a meta-regression was conducted to identify measured methodological factors that could explain between-study variability.
Over 60 perinatal and neonatal factors were examined. Factors associated with autism risk in the meta-analysis were abnormal presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, congenital malformation, low 5-minute Apgar score, feeding difficulties, meconium aspiration, neonatal anemia, ABO or Rh incompatibility, and hyperbilirubinemia. Factors not associated with autism risk included anesthesia, assisted vaginal delivery, postterm birth, high birth weight, and head circumference.
There is insufficient evidence to implicate any 1 perinatal or neonatal factor in autism etiology, although there is some evidence to suggest that exposure to a broad class of conditions reflecting general compromises to perinatal and neonatal health may increase the risk. Methodological variations were likely sources of heterogeneity of risk factor effects across studies.
Comments
Intrapartum oxytocin administration and neonate sensitive period disruption could also explain increase in autism risk.
Gardener, Spiegelman and Buka conclude after their careful Meta- Analysis that there is some evidence to suggest that exposure to multiple perinatal and neonatal complications may increase autism risk. However no attention is paid to two very common perinatal manipulations that could help explain the finding. The first one is fetal Intrapartum exposure to synthetic oxytocin (Pittocin). Oxytocin has been shown to play a central role in the regulation of affiliate social behavior, including sexual behavior, mother infant bonding and social memory and recognition. Following normal physiological vaginal birth highest levels of plasmatic endogenous oxytocin are achieved (1). This has been related to the presence of a sensitive period which seems to facilitate bonding and initial mother and newborn attachment (2). Perinatal OT manipulation can have life long lasting effects on social and sexual behaviors in animal models (3). The effect appears to be sexually dysmorphic (4). Pittocin is the most commonly drug used worldwide to hasten labor contractions. It is possible that synthetic OT can cross the maternal placenta and the infantile blood brain barrier at birth, causing and effect on neonatal OT receptors at a very critical time (5). Dysregulation of oxytocinergic system has been observed in individuals with autistic disorders. Epigenetic mechanisms in the neonate sensitive period could be the partial explanation of oxytocin and vasopressin dysfunction observed in autism (6). The second common perinatal manipulation is disruption of the neonate sensitive period. Recent evidence demonstrates the existence of a short, early sensitive period after delivery lasting only 2 to 3 hours (7) as it was suggested by Klaus almost 40 years ago (8). If undisturbed during this period and left on the mother's chest skin to skin the newborn typically crawls to the breast, recognizes the mother's face and eye to eye contact is established spontaneously in the dyad. At this time in the infants, the levels of catecholamines are very high. These neuroendocrine patterns may allow a unique ability to "learn or form memories" which may have some similarities to imprinting or formation of conditional effects (7). Neonate sensitive period can be disturbed by the type of birth or by the type of newborn care offered immediately after birth. Elective cesareans with no prodromal labor, maternal separation, absence of skin to skin contact, or formula feeding are all situations where spontaneous oxytocin secretion will be decreased in the critical time following delivery(9,10) . Could the increase in autism prevalence be related to the medicalisation of childbirth? Routine use of intrapartum oxytocin, mother child separation on the sensitive period, lack of skin to skin contact, effect of other drugs, or even the cesarean epidemic could all well cause a disruption of the oxytocinergic system at a very critical period of time with possible long lasting effects. Further research is needed on the factors that maximize normal births and healthy outcomes for mothers and babies (11), not only to improve the experience but also to bring some light on the perinatal factors of autism. Newborn babies should never be separated from their mothers except for significant medical reasons and should be placed skin-to-skin as soon as possible after birth
(1) Russell JA, Douglas AJ, Ingram CD. Brain preparations for maternity--adaptive changes in behavioral and neuroendocrine systems during pregnancy and lactation. An overview. Prog Brain Res 2001;133:1-38. (2) Klaus MH. Commentary: An early, short, and useful sensitive period in the human infant. Birth 2009 Jun;36(2):110-112. (3) Carter CS. Developmental consequences of oxytocin. Physiol Behav 2003 Aug;79(3):383-397. (4) Carter CS, Boone EM, Pournajafi-Nazarloo H, Bales KL. Consequences of early experiences and exposure to oxytocin and vasopressin are sexually dimorphic. Dev Neurosci 2009;31(4):332-341. (5) Wahl RU. Could oxytocin administration during labor contribute to autism and related behavioral disorders?--A look at the literature. Med Hypotheses 2004;63(3):456-460. (6) Gurrieri F, Neri G. Defective oxytocin function: a clue to understanding the cause of autism? BMC Med 2009 Oct 22;7:63. (7) Bystrova K, Ivanova V, Edhborg M, Matthiesen AS, Ransjo-Arvidson AB, Mukhamedrakhimov R, et al. Early contact versus separation: effects on mother-infant interaction one year later. Birth 2009 Jun;36(2):97-109. (8) Klaus MH, Jerauld R, Kreger NC, McAlpine W, Steffa M, Kennel JH. Maternal attachment. Importance of the first post-partum days. N Engl J Med 1972 Mar 2;286(9):460-463. (9) Matthiesen AS, Ransjo-Arvidson AB, Nissen E, Uvnas-Moberg K. Postpartum maternal oxytocin release by newborns: effects of infant hand massage and sucking. Birth 2001 Mar;28(1):13-19. (10) Wiklund I, Norman M, Uvnas-Moberg K, Ransjo-Arvidson AB, Andolf E. Epidural analgesia: breast-feeding success and related factors. Midwifery 2009 Apr;25(2):e31-8. (11) Johanson R, Newburn M, Macfarlane A. Has the medicalisation of childbirth gone too far? BMJ 2002 Apr 13;324(7342):892-895.
Conflict of Interest:
The author has received a grant from the Spanish Ministerio de Ciencia e Innovacion to research the effects of intrapartum oxytocin administration on newborn behavior
The Auditory System is Most Vulnerable
Many thanks to Gardener et al. for undertaking this analysis of perinatal factors reported as predispositions for autism. Oxygen insufficiency is the great worry about any complication of pregnancy or birth, and Gardener et al. state, "The obstetrical complications that have emerged as significant risk factors for autism in the current meta- analysis suggest a possible role of fetal and neonatal hypoxia." [1, p e7].
Oxygen insufficiency is the great worry about any complication of childbirth. Gardener et al. suggested a possible disruption of dopamine in the brain. However, the effects of hypoxia on the brain were reported in several papers published more than 40 to 50 years ago.
Prominent ischemic injury of auditory nuclei in the brainstem was found in monkeys subjected to a brief period of asphyxia at birth [2, 3]. Similar patterns of damage have been reported in human infants [4]. The asphyxiated monkeys appeared to recover following initial difficulties with motor control. However, manual dexterity remained impaired, and brain maturation did not follow a normal course in monkeys allowed to survive for several months or years [5].
No one expects monkeys to learn to speak, but at least 12 case reports have been published of people who lost the ability to understand speech following injury of auditory nuclei in the midbrain, the inferior colliculi [6]. How much more serious would such injury be for an infant?
Autism is associated with many causes: prenatal exposure to valproic acid, genetic metabolic disorders such as phenylketonuria (PKU), and encephalitic infections. The inferior colliculi and other nuclei in the brainstem auditory pathway have higher blood flow than any other area of the brain and are thus susceptible to injury from toxic substances in the circulation as well as oxygen insufficiency [7].
Kulesza et al. (2011) have reported finding malformation of the superior olivary nuclei in the auditory pathway in post mortem brains from people who were diagnosed with autism in childhood [8]. How all of autism's etiologic factors affect the brain and prevent normal language development needs to be looked at. Prenatal use of medications and other chemical substances, as well as interventions used in obstetrics that may prevent normal transition from placental to pulmonary respiration must be investigated as possible causes of the recent increase in autism prevalence.
References:
[1] Gardener H, Spiegelman D, and Stephen L. Buka SL. Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics; published online July 11, 2011. http://pediatrics.aappublications.org/content/early/2011/07/06/peds.2010- 1036
[2] Ranck JB, Windle WF. Brain damage in the monkey, Macaca mulatta, by asphyxia neonatorum. Exp Neurol. 1959 Jun;1(2):130-54.
[3] Myers RE. Two patterns of perinatal brain damage and their conditions of occurrence. Am J Obstet Gynecol. 1972 Jan 15;112(2):246-76.
[4] Leech RW, Alvord EC Jr. Anoxic-ischemic encephalopathy in the human neonatal period, the significance of brain stem involvement. Arch Neurol. 1977 Feb;34(2):109-13.
[5] Faro MD, Windle WF. Transneuronal degeneration in brains of monkeys asphyxiated at birth. Exp Neurol. 1969 May;24(1):38-53.
[6] I have discussed these on my website at http://conradsimon.org/Language.html
[7] Kety SS. Regional neurochemistry and its application to brain function. Bull N Y Acad Med. 1962 Dec;38:799-812. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1804882/?tool=pubmed
[8] Kulesza RJ Jr, Lukose R, Stevens LV. Malformation of the human superior olive in autistic spectrum disorders. Brain Res. 2011 Jan 7;1367:360-71.
Conflict of Interest:
Mother of a son with autism