Benzodiazepines: A Risk Factor
in Sudden Infant Death?
Susan Bibby
BEAT THE BENZOS CAMPAIGN
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Croydon, UK, November 2000
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Benzodiazepines are still being prescribed to pregnant women today although a recent reminder from the CSM in 1997[1] may have caused some reduction. In 1994 an estimated 30-40% of all pregnant women were taking antianxiety/hypnotic drugs at some stage of pregnancy, the majority of which were benzodiazepines[2]. If this figure takes into account the numbers of pregnant benzodiazepines misusers it may be an underestimate as illicit benzodiazepine use continues to rise.
It is established that prenatal benzodiazepine exposure can be dangerous to the newborn in two ways:
from the direct effects of the drug, (the baby cannot fully metabolise it).
neonatal withdrawal syndrome.
Both can be severe and prolonged, needing specialist treatment.
A link between Sudden Infant Death Syndrome (SIDS) and benzodiazepine exposure during pregnancy has not as yet been fully investigated but sufficient evidence points to benzodiazepines as a contributory factor.
The recent increase in drug-related deaths from respiratory failure in drug misusers has been attributed to the widespread use of benzodiazepines with opiates[3].
As it is established that prenatal opiate exposure increases the risk of SIDS,[4] this is compounded in a baby prenatally exposed to benzodiazepines and opiates.
The following suggest benzodiazepines may be a risk factor in SIDS:
The foetus receives benzodiazepines through the placenta at high concentrations and some babies cannot metabolise it after birth[5], resulting in apnoea, respiratory depression, hypoactivity, "floppy" muscles, hypothermia and feeding difficulties, which can last for months.[2]
Levels of active benzodiazepines and metabolites have been measured in infants ten week old and beyond.
The unpredictable nature of benzodiazepine metabolism is poorly understood. It has been observed[6] in prenatally exposed rats that benzodiazepines concentrate in the brain at birth, migrate to the major organs and then return to the brain. It is not known if this occurs in human babies but an unpredictable course of toxicity and abstinence syndrome of late onset have been observed.
Disturbances in respiratory function and thermoregulation[7] have been associated with SIDS and both can be caused by prenatal benzodiazepine exposure in the neonate. Benzodiazepine-induced respiratory disturbance is only one aspect of many hazards faced by newborns exposed to these drugs.
It established that benzodiazepines act therapeutically by altering the function of the GABA system in the brain.[8] Return of receptors to the pre-drug state can be protracted – in part explaining the lengthy withdrawal syndrome[9] (months to years), associated with these drugs.
The pontine pneumotaxic centre (Kollicker-Fuse) in the brain modulates respiratory rhythm and also processes respiratory reflexes including the Hering Breuer reflex and the diving reflex. The diving reflex causes apnoea, slowed heart rate and peripheral vasoconstriction. Recent research shows that GABAa receptors play a primary role in the control of this system. The blockade of GABAa by the administration of bicuculline in the Kollicker-Fuse area results in apnoea[10].
In a letter to the Lancet,[11] one of the first to warn of the dangers of prenatal benzodiazepine exposure came from Dr Nigel Speight who, describing a baby admitted to special care due to benzodiazepine exposure, stated that the baby might have died on a postnatal ward of an apnoeic episode had he not been admitted to a special care nursery.
An increased death rate (many of them sudden) in children with epilepsy treated with nitrazepam has been reported[12] and the incidence of apnoea, sudden death and respiratory difficulties in these fatalities was high.
Death or serious incidents with the use of benzodiazepines alone[13], or in combination with opiates in surgical procedures due to hypoxia, apnoea, respiratory distress and laryngospasm have been reported[14].
Benzodiazepines can cause or exacerbate apnoea and respiratory problems[15] reflected in both a manufacturer's recent product information leaflet[16] and in frequent anecdotal reports.
Successful reversal of the above effects of benzodiazepines with flumazenil (a benzodiazepine antagonist) in prenatally exposed babies[17,18,19], patients undergoing surgical procedures[20], and in overdosage, isolates the benzodiazepine as the primary cause.
In light of the above and in spite of a lack of empirical data newborn babies of benzodiazepine using mothers are being exposed to unacceptably high risks compounded by the addition of opiates. Currently little is being done to inform potential parents of these risk particularly those misusing benzodiazepines.
Significant advances in understanding SIDS have dramatically reduced its incidence but should this exclude investigation into a link between benzodiazepines and SIDS?
© Susan Bibby 2000
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References
Committee on the Safety of Medicines: Reminder: Avoid Benzodiazepines in Pregnancy and Lactation, 1997.
McElhatton, Patricia R. The Teratology information Service, The UDMS, St Thomas' Hospital, London, England. Reproductive Toxicology Review. The Effects of Benzodiazepine Use During Pregnancy and Lactation. Reproductive Toxicology, Vol. 8. No. 6. pp 461-475. 1994.
Advisory Council on Misuse of Drugs, report: Reducing Drug-Related Deaths, 1999.
Ward SLD et al. "Abnormal Sleeping Patterns in infants of substance Abusing Mothers": American Journal of Diseases of Children (1987).
Weber LWD: Benzodiazepines in Pregnancy – Academic Debate or Teratogenetic Risk? Gesellschaft für Strahlen und Umveltforschung G.m.b.H. München, Institut für Biologie, Abteilung Nuklearbiologie, Ingolstadter Landstraße 1, D-8042 Nürnrberg, Germany.
Professor Carol K. Kellogg: Personal correspondence, Department of Brain and Cognitive Sciences, University of Rochester, New York. 1997-8.
Fleming PJ, Azaz Y, Wingfield R: Development of Thermoregulation in Infancy: Possible Implications for SIDS. Department of Child Health, Bristol Maternity Hospital. J. Clin. Pathol.,1992 Nov;45 (11 Suppl):17-19 (ISSN: 0021-9746).
Messer Jr. WS: Professor of Medicinal and Biological Chemistry, The University of Toledo: MBC 3320, GABA Systems, Feb 2000.
Ashton CH. DM, FRCP: Protracted Withdrawal From Benzodiazepines: The Post-Withdrawal Syndrome. Psychiatric Annals, 25:3, Mar 1995, pp 174-179.
Mathias Dutschmann and Horst Herbert: Department of Animal Physiology, University of Tübingen, Auf Der Morgenstelle 28, D-72076 Tübingen, Germany. NMDA and GABAa receptors in the rat Kollicker-Fuse area control cardiorespiratory responses evoked by trigeminal ehtmoidal nerve stimulation. Journal of Physiology, (1998), 510.3, pp. 793-804.
Dr ANP Speight: Children's department, Newcastle General Hospital, Newcastle Upon Tyne, NE4 6BE: Floppy Infant Syndrome and Maternal Diazepam and/or Nitrazepam. The Lancet, October 22, 1977.
Pertti J. Rintahaka, Jo Anne Nakagawa, D. Alan Shewmon, **Penntti Kyyronen and W. Donald Shields: Incidence of Death in Patients with Intractable Epilepsy During Nitrazepam Treatment. UCLA School of Medicine, Los Angeles, California, USA: and *University of Helsinki for Children and adolescents Neurology & **Institute of Occupational Health, Helsinki, Finland. Epilepsia, 40(4): 492-496, 1999.
Davis DP, Hamilton RS, Webster TH: Department of Emergency Medicine, University of California at San Diego, USA. shrimptaco@aol.com – Reversal of Midazolam-Induced Laryngospasm with Flumazenil.
Bailey PL, Pace NL, Ashburn MA, Moll JW, East KA, Stanley TH: Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, 84132: Frequent Hypoxemia and Apnea after Sedation with Midazolam and Fentanyl. Anesthesiology,1990 Nov; 73(5): 826-30 (ISSN: 0003-3022).
Guilleminault C: Stanford University Medical Centre, California: Benzodiazepines, Breathing and Sleep. Am J Med, 1990 Mar 2 ; 88(3A): 25s-28s.
Shibata T, Kubota N, Yokoyama H: Dept. of Anaesthesia, Tokyo General Hospital, School of Medicine, Kawasaki 211, Japan. Japanese Journal of Anaesthesiology, 1994, Vol/Iss/pg 43/4 (572 574 ISSN: 0021-4892.
Stahl MMS, Saldeen P, Vinge: Reversal of foetal benzodiazepine intoxication using Flumazenil. British Journal of Obstetrics and Gynaecology, Vol 100, Pages 185-188. 01 February, 1993. Case report.
Richard P, Autret E, Bardol J, Soyez C, Barbier P, Jonville A: Dept. Of Neonatology, Tours Cedex, France: The use of Flumazenil in a neonate. Journal of Toxicology, Clinical Toxicology, Vol 29, Page 137-140, March 1991.
Talk Radio UK Interview with Mike Dicken and Susan Bibby, December 5, 1998.
Benzodiazepines: A Hidden Epidemic, May 2003 by Susan Bibby.
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