alcohol , drug use and pregnancy outcome

7/30/2019 Alcohol , Drug Use and Pregnancy Outcome

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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

concern about the influence

of alcohol on pregnancy

outcome was revived in the

early 1970s when a series of

articles by researchers was

published.5,6,7. These reportsculminated in the

description, by Jones and

Smith 8, of a fetal alcohol

syndrome (the FAS) among

the offspring of severely and

chronically alcoholic

mothers, who continued to

drink throughout pregnancy.

A study in USA has shown that

there is a seven point deficit

in a childs IQ where its

mother has taken just oneunit of alcohol daily during

pregnancy.9

The principal characteristics

that have been associated

with the FAS are:

pre-natal and post-natalgrowth retardation;

central nervous systemdysfunction including

mental deficiency,

neurological problems

and behavioural

dysfunction;

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 ordinarybeer, 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.

FETAL ALCOHOL SYNDROME: A combination of birth

defects, including organ deformities and mental, motor,

and/or growth retardation, that results from maternal

alcohol abuse as well as some additional, but less

important, factors.

However where the syndrome is diagnosed, the alcoholabuse is most often accompanied by adverse

environmental circumstances. Foetuses conceived by

heavy drinkers are more likely to miscarry, are smaller at

birth, do not thrive so well initially and are poor suckers,

whether from the bottle or breast. It is not uncommon to

find that as the child reaches primary school-age, he will

be less intelligent and be less integrated with his peers.

Alcoholic mothers are likely to have infants suffering from

fetal alcohol syndrome, which is characterized by

deformities of the heart and joints, face (short eyelid slits

and abnormal jaw protrusion), and hand (altered palmar

crease patterns), lags in motor development and motor

dysfunction, and severe mental handicap. Even moderate

drinking less than one drink per day has been found to

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 alcoholicbeverages during pregnancy can cause birth defects.


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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 follow-

up 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 congenitalmalformations, 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.

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 largenumber 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)

Pregnancy Variables Paris S. California Boston Denver London

Gestation - + + + NR

Birth-weight + + - - +

Small for dates + NR - - +

Congenital abnormality - NR - - NR

Still-birth + NR - - NR

+ = statistically significant negative association between alcohol and the outcome

reported- = 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


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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 andresponse 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 non-

treated 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 isknown 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 eithermechanism 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 associatedwith 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 neuro-

apoptotic 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 drinkingcontext, 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

1 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-oldchildren. Developmental Psychology, 20, [pp., 533-542]; 1984.

2 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.

3 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.

4 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.

5 Ulleland, C.N. The offspring of alcoholic mothers.Ann. NY Acad. Sci. 197: [pp., 167-169.] 1972.

6 Jones, K.L; Smith, D.W.; Ulleland, C.N.; & Streissguth, A.D. Pattern of malformation in offspring

of chronic alcoholic mothers. Lancet1: [pp., 1267-1271] 1973.

7 Jones, K.L; & Smith, D.W. Recognition of the fetal alcohol syndrome in early infancy. Lancet; 2:

[pp., 999-1001] 1973.

8 Jones, K.L; & Smith, D.W. The fetal alcohol syndrome. Teratology; 12: [pp., l-l0]1975.

9 Glenville, M. Health Professionals Guide to Preconceptual Care. Foresight; Godalming,

c1995.

10 Roman, Eve. Hazards in Pregnancy with Specific Reference to Alcohol. InHosking, 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.

11 Royal College of Obstetricians and Gynaecologists, Report of the; Alcohol and Pregnancy,

1997.

12 Niswander, K.R.; & Gordon M. The women and their pregnancies. Philadelphia: W. B.

Saunders, 1972.

13 Neugut R.H. Epidemiological appraisal of the literature on the fetal alcohol syndrome in

humans. Early Hum. Dev.; 5: [pp., 411-422]. 1981.

14 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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15 Poland, R.E. Effects of maternal ethanol consumption in rats on basal and rhythmic pituitary-

adrenal function in neonatal offspring. Psychoneuro-endocrinology; 7(1); [pp., 49-58] 1982.

16 Goodwin, D.W. Alcoholism. In Hobson, J.A. [Ed.]Abnormal States of Brain and Mind. Boston,

USA; & Basel, Birkhuser, 1989.

17 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.

18 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.

19 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.

20 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.

21 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.

22 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.

23 Tenkova T &Olney JW. Ethanol-induced apoptosis in the developing visual system during

synaptogenesis. Invest Ophthalmol Vis Sci; 2003.

24 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.

25 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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