Alcohol, Drug Use and Pregnancy Outcome

Alan Challoner MA(Phil) MChS

Current concerns about the effects of alcohol consumption on the unborn child may be assessed from this summary of some of the research that has been carried out since the 1970s. The suggestion that alcohol has an adverse effect on pregnancy and child development has a long history. Modern FETAL ALCOHOL SYNDROME: A combination of birth concern about the influence defects, including organ deformities and mental, motor, of alcohol on pregnancy and/or growth retardation, that results from maternal outcome was revived in the alcohol abuse as well as some additional, but less early 1970s when a series of important, factors. articles by researchers was published.5,6,7. These reports However where the syndrome is diagnosed, the alcohol culminated in the abuse is most often accompanied by adverse description, by Jones and environmental circumstances. Foetuses conceived by Smith 8, of a fetal alcohol heavy drinkers are more likely to miscarry, are smaller at syndrome (the FAS) among birth, do not thrive so well initially and are poor suckers, the offspring of severely and whether from the bottle or breast. It is not uncommon to chronically alcoholic find that as the child reaches primary school-age, he will mothers, who continued to be less intelligent and be less integrated with his peers. drink throughout pregnancy. Alcoholic mothers are likely to have infants suffering from A study in USA has shown that fetal alcohol syndrome, which is characterized by there is a seven point deficit deformities of the heart and joints, face (short eyelid slits in a childs IQ where its and abnormal jaw protrusion), and hand (altered palmar mother has taken just one crease patterns), lags in motor development and motor unit of alcohol daily during dysfunction, and severe mental handicap. Even moderate pregnancy.9 drinking less than one drink per day has been found to The principal characteristics that have been associated with the FAS are: pre-natal and post-natal growth retardation; central nervous system dysfunction including mental deficiency, neurological problems and behavioural dysfunction; be related to attentional deficits in children at four years of age, Streissguth et al., 1,2, decreased fetal growth, and increased risk of miscarriage, Mills et al., 3. Results of animal studies by Furey also show serious problems resulting from single episodes of heavy alcohol consumption around the time of conception.4 In view of these research findings, the USA Surgeon General has warned that all pregnant women should avoid alcohol entirely. Some areas, such as New York City, have passed ordinances that require all bars, restaurants, and liquor stores to post notices such as; Warning: Drinking alcoholic beverages during pregnancy can cause birth defects.

a characteristic pattern of facial anomalies including the nose, mouth, ears and jaw; and various other malformations mainly of the skeletal, urogenital and cardiac systems.

The effects are dose-related and therefore every woman must realise the potential hazard for her child-to-be.10 Research from the late 1990s11 indicates that pregnant women may drink a small amount of alcohol without harming the foetus. The acceptable level that was considered reasonable was one unit per day (i.e. small glass of wine; half a pint of ordinary beer, or a single measure of spirits. More than this may hinder the growth of the foetus, leading to a smaller baby. Consumption of over 15 units a week may be associated with intellectual impairment. Page 1 of 6

The Seattle research group12, examined intellectual development in the children of mothers who were addicted to alcohol and reported a significantly reduced IQ at 7 years of age. It is not clear whether the investigators who made this assessment knew the alcohol status of the mother. Moreover, 32% (6/19) of the alcoholics children were apparently lost to followup before 7 years of age compared with none of the controls.13 However, despite the small numbers and the questionable nature of the comparison, the authors recommended that:
serious consideration should be given to the early termination of pregnancy in severe chronically alcoholic women . . . [ since] . . . the offspring of chronic alcoholic women, whose development and function are often permanently damaged by their adverse intrauterine environment, frequently became a problem for society in postnatal life.

These and other studies reported that the babies of women who drank excessively during pregnancy were disadvantaged in some way. All reported that the birth-weight of babies was significantly reduced among women considered to be alcohol abusers. There are however some inconsistencies in the findings of some studies. Two, the Cleveland and Buffalo studies, agree that the babies of alcohol abusers tend to be small for dates. The Cleveland and Seattle groups found an overall increase in the rate of congenital malformations, but the Buffalo group did not. The Cleveland group found no increase in perinatal mortality whereas the Seattle group did. Moreover, the Seattle study retrospectively diagnosed 32% (6/19) cases of the FAS, whereas the Cleveland study retrospectively diagnosed 2.5% (5/204). These discrepancies may reflect the fact that different definitions of alcoholism were used. Only 0.04% of women were classified alcoholic by the Seattle researchers compared with 1.7% by the Cleveland researchers. The outcome of moderate drinking in pregnancy is clear following reports of investigations that were set up to look at these effects. A large number of epidemiological studies have been reported on and the findings from five are summarized in the Table below.

Pregnancy Variables Gestation Birth-weight Small for dates Congenital abnormality Still-birth + reported

Paris + + +

S. California + + NR NR NR

Boston + -

Denver + -

London NR + + NR NR

= statistically significant negative association between alcohol and the outcome

- = no statistically significant negative association between alcohol and the outcome reported NR = not reported Reported association between various aspects of pregnancy outcome and alcohol consumption in early pregnancy [after Roman] 10

The studies outlined in the Table above show inconsistencies. Some of the reasons for these may be that the studies were conducted at different times, in different places, by different people using different methodologies. The inconsistencies are however important. A large number of other studies, besides those in the Table, have been published and there is clearly no consensus about the relationship between moderate drinking and adverse pregnancy outcome. (Roman, Idem) Page 2 of 6

Several studies of the effect of alcohol have been made using pregnant rats. Of those that were fed liquid alcohol diets during pregnancy the following results were found: 140 subjects were tested for activity irregularities ten days after birth, passive avoidance learning, and spontaneous alternation in a T-maze. The subjects showed age-related increased activity; but deficits in passive avoidance learning and response perseveration that were not age-related. Abel suggests that the exposure to alcohol brought about a developmental delay in the response inhibition mechanisms underlying activity. They also were less maternally responsive than nontreated controls.14 Poland found that the neuro-toxic effects of the fetal alcohol exposure on neuro-endocrine function may become evident when there is a stress challenge. 15 Alcoholism runs in families, and does so even when the children of alcoholics are separated from their parents and raised by non-alcoholic adoptive parents. Twin studies suggest genetic factors. Childhood behaviour problems weakly predict future alcoholism.16 Recent concerns should allow for more current research to be considered as there may be a differing view to be obtained. An article in the issue of Science, dated 11th February 2000 reported that a single exposure to high levels of ethanol (the alcohol in beer, wine and spirits) can kill nerve cells in the developing brain. The researchers found that the rat brain is sensitive to this toxic effect during a brain development stage that corresponds to the brain growth spurt in humans. This is known as synaptogenesis because it is the time when brain cells form most of their interconnections, the brain growth spurt lasts from about the sixth month of pregnancy to a child's second birthday. The investigators believe that the discovery that cells can die after a single episode of alcohol intoxication means it would be prudent for expectant mothers to avoid alcohol intoxication during pregnancy. The investigators also studied the mechanism of this alcohol-induced brain cell death. It is known that alcohol can interfere with certain transmitter systems in the brain. The systems use chemical molecules, such as glutamate and GABA, to activate nerve cell receptors and transmit messages from one cell to another. In research reported in 1999, in Science, Olney and colleagues found that drugs called NMDA antagonists, which interfere with glutamate transmission in the same way that alcohol does, have a similar cell-killing effect in the infant rat brain when given as a single high dose. In the current study, the investigators found that drugs that excessively activate GABA receptors, as alcohol does, also can kill nerve cells in the infant rat brain. This evidence documents that alcohol acts by two mechanisms blockade of glutamate transmission and excessive stimulation of GABA transmission. By combining these two mechanisms, it produces a compound pattern of damage that is greater than either mechanism would produce by itself.17 There are other concerns that were highlighted by this research team. Much of the significance of these findings comes from the fact that alcohol is so widely used throughout the world. Numerous other drugs act either by blocking glutamate receptors or activating GABA receptors, and many of these drugs are drugs of abuse and/or are used in paediatric medicine as sedatives, anticonvulsants or anaesthetics. Drugs of abuse that block NMDA glutamate receptors include phencyclidine (PCP or "angel dust"), ketamine (special "K") and nitrous oxide (laughing gas). Both ketamine and nitrous oxide are used frequently in paediatric anaesthesia. GABA receptor activators that are frequently abused and/or used in paediatric anaesthesia include benzodiazepines, barbiturates, isoflurane, and propofol.

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The death of neurons by apoptosis18 occurs naturally. It enables the brain to get rid of unhealthy cells or cells that are not needed for normal brain development. Alcohol and these other drugs don't just cause cells that are going to die anyway to die more quickly; they cause cells that never would have died under normal circumstances to commit suicide and millions are involved.17 These mechanisms may contribute to the wide variety of neurological and psychiatric symptoms seen in individuals with fetal alcohol syndrome. Symptoms range from hyperactivity and learning disabilities in childhood to depression or severe psychosis in adulthood. Olney believes the variety of symptoms may be explained by the timing of alcohol exposure. In the rat, he found that different populations of neurons were vulnerable at different times during synaptogenesis. Some psychiatric and neurological disorders are thought to originate from events that occur during development and the research will allow there to be a better understanding and provide some correlations between damage to specific cell populations during development and subsequent neuropsychiatric problems. 17 In a further episode of research, Olney and his colleagues have reported on the neurotoxic effects of ethanol on the human fetal brain and have reported that a single episode of ethanol intoxication lasting for several hours can trigger a massive wave of apoptotic neuro-degeneration in the developing rat or mouse brain. The window of vulnerability coincides with the developmental period of synaptogenesis; in humans this extends from the sixth month of gestation to several years after birth. 19 They propose that the N-methyl-D-aspartate (NMDA) antagonist and gamma-aminobutyric (GABA)mimetic properties of ethanol are responsible for its apoptogenic action, because they have found that other drugs that block NMDA glutamate receptors or mimic GABA at GABA(A) receptors also trigger apoptotic neuro-degeneration in the developing brain. These findings have clinical significance, not only because they can explain the reduced brain mass and neurobehavioral disturbances associated with the human FAS, but because many agents in the human environment, other than ethanol, have NMDA antagonist or GABAmimetic properties. This research has been continued by Wozniak and colleagues and they have reported that binge-like exposure of infant mice to ethanol on a single post-natal day triggered apoptotic death of neurons from diencephalic structures that comprise an extended hippocampal circuit important for spatial learning and memory. The ethanol exposure paradigm yielding these neuronal losses caused profound impairments in spatial learning and memory at one month of age. This impairment was significantly attenuated during subsequent development, indicating recovery of function. Recovery was not associated with increased neurogenesis, suggesting plastic reorganization of neuronal networks compensated for early neuronal losses. They hypothesize that neuro-apoptotic damage in homologous regions of human brain underlies cognitive deficits in FAS and the human brain of FAS victims has a similar capacity to affect functional recovery.20 It was later reported by Young and Olney that they had sought to determine what magnitude and duration of blood ethanol elevation is required to trigger a minimal neuroapoptotic response. They found that a rise in blood ethanol to a level in the range of 50 mg/dl for a duration of 30 to 45 min was sufficient to trigger a significant neuro-apoptosis response deleting approximately 20,000 neurons per infant mouse brain. Since blood ethanol elevations in this range are commonly achieved by humans in a social drinking context, a mother with only a moderate drinking habit might expose her foetus to such elevations on multiple occasions during pregnancy.21

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Earlier, Dikranian et al described the time course of neuro-degeneration and window of vulnerability for Purkinje cells and other neurons in the cerebellar cortex, deep cerebellar nuclei, and two related brainstem nuclei (nucleus pontis, inferior olivary complex),and demonstrated that the cell death process in each case is unequivocally apoptotic. They concluded that exposure of infant rats or mice to ethanol on a single occasion during synaptogenesis can kill Purkinje cells, and many other neuronal populations at all levels of the developing neuraxis, and in each case the mechanism of cell death is apoptosis.22 Tenkova and Olney have reported that during synaptogenesis, a single ethanol intoxication episode triggers apoptotic cell death of neurons at all levels of the visual system from retina to the visual cortex.23 A 2010 report by Yuede and colleagues24 reports that the developing human brain may be exposed to NMDA antagonists through drug-abusing mothers who use Phencyclidine. 25

Streissguth, A. P.; Martin, D. C.; Barr, H. M.; Sandman, B. M.; Kirchner, G.L.; & Darby, B. L. Intrauterine alcohol and nicotine exposure: Attention and reaction time in four-year-old children. Developmental Psychology, 20, [pp., 533-542]; 1984. Streissguth, A P., Barr, H. M., Sampson, P. D., Darby, B. L., & Martin, D. C. IQ at age four in relation to maternal alcohol use and smoking during pregnancy. Developmental Psychology. 25( 1), [pp., 3 - 11]. l989. Mills, J. L.; Braubard, B. I.; Harley, E. E.; Rhoads, G. G.; & Berendes, H. W. Maternal alcohol consumption and birth weight: How much drinking during pregnancy is safe? Journal of the American Medical Association, 252, [pp., 1857-1879. ] 1984. Furey, E. M. The effects of alcohol on the fetus. In H. E. Fitzgerald & M. G. Walraven [Eds.], Human Development 84/85 Guilford, CT: Dushkin. 1984. Ulleland, C.N. The offspring of alcoholic mothers. Ann. NY Acad. Sci. 197: [pp., 167-169.] 1972. Jones, K.L; Smith, D.W.; Ulleland, C.N.; & Streissguth, A.D. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1: [pp., 1267-1271] 1973. Jones, K.L; & Smith, D.W. Recognition of the fetal alcohol syndrome in early infancy. Lancet; 2: [pp., 999-1001] 1973. Jones, K.L; & Smith, D.W. The fetal alcohol syndrome. Teratology; 12: [pp., l-l0]1975. Glenville, M. Health Professionals Guide to Preconceptual Care. Foresight; Godalming, c1995. Roman, Eve. Hazards in Pregnancy with Specific Reference to Alcohol. In Hosking, Gwilym; & Murphy, Glynis. [Eds.]; Prevention Of Mental Handicap: A World View. International Congress And Symposium Series: Number 112. Royal Society Of Medicine Services; London, 1987. Royal College of Obstetricians and Gynaecologists, Report of the; Alcohol and Pregnancy, 1997. Niswander, K.R.; & Gordon M. The women and their pregnancies. Philadelphia: W. B. Saunders, 1972. Neugut R.H. Epidemiological appraisal of the literature on the fetal alcohol syndrome in humans. Early Hum. Dev.; 5: [pp., 411-422]. 1981. Abel, E.L. In utero alcohol exposure and developmental delay of response inhibition. Alcoholism: Clinical & Experimental Research; 6(3); [pp., 369-376] 1982.

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Poland, R.E. Effects of maternal ethanol consumption in rats on basal and rhythmic pituitaryadrenal function in neonatal offspring. Psychoneuro-endocrinology; 7(1); [pp., 49-58] 1982. Goodwin, D.W. Alcoholism. In Hobson, J.A. [Ed.] Abnormal States of Brain and Mind. Boston, USA; & Basel, Birkhuser, 1989. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Hrster F, Tenkova T, Dikranian K, Olney JW. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science. 2000 Feb 11;287(5455):1056-60. Apoptosis A process of programmed cell death by which cells undergo an ordered sequence of events which lead to death of the cell, as occurs during growth and development of the organism, as a part of normal cell aging, or as a response to cellular injury. Olney JW, Wozniak DF, Farber NB, Jevtovic-Todorovic V, Bittigau P, Ikonomidou C. The enigma of fetal alcohol neurotoxicity. Ann Med. 2002;34(2):109-19. Wozniak DF, Hartman RE, Boyle MP, Vogt SK, Brooks AR, Tenkova T, Young C, Olney JW, Muglia LJ. Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults. Neurobiol Dis. 2004 Dec;17(3):403-14. Young C, & Olney JW. Neuroapoptosis in the infant mouse brain triggered by a transient small increase in blood alcohol concentration. Neurobiol Dis. 2006 Jun;22(3):548-54. Dikranian K, Qin YQ, Labruyere J, Nemmers B, Olney JW. Ethanol-induced neuro-apoptosis in the developing rodent cerebellum and related brain stem structures. Brain Res Dev Brain Res. 2005 Mar 22;155(1):1-13. Tenkova T & Olney JW. Ethanol-induced apoptosis in the developing visual system during synaptogenesis. Invest Ophthalmol Vis Sci; 2003. Yuede CM.; Wozniak DF.; Creeley CE.; Taylor GT.; Olney JW. & Farber NB. Behavioral consequences of NMDA antagonist-induced neuroapoptosis in the infant mouse brain. PLoS One; 2010. Phencyclidine (a complex clip of the chemical name 1-(1-phenylcyclohexyl)piperidine), commonly initialized as PCP and known colloquially as angel dust or wet, is a recreational dissociative drug. Formerly used as an anesthetic agent, PCP exhibits both hallucinogenic and neurotoxic effects.

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