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Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
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Motherisk Newsletters: Fall 2000, No. 12
Motherisk Launches FACE - Fetal Alcohol Canadian Expertise
This issue of the Motherisk newsletter marks the launch of our fetal alcohol research group. Dubbed FACE (Fetal Alcohol Canadian Expertise) we believe it is the first invitation to all Canadian researchers studying the fetal burden of maternal drinking to share a similar agenda. As reflected in the activities of the Motherisk program that are highlighted in this newsletter, fetal alcohol research spans from molecular medicine to health economy, from metabolic etiologies to child neurodevelopment.
We believe that by collaborating with colleagues throughout the country we can build on existing expertise and resources, enhance the ability to secure research funding and develop crucial new knowledge.
We may also have greater impact as advocates when addressing the various levels of governments that must deal with the tremendous burden of this life-long disability.
If you have or are aware of a Canadian program directly or indirectly involved in fetal alcohol research, please let us know. This invitation is open to researchers in all fields of medical and social sciences.
Fetal alcohol syndrome and other alcohol related effects are the most common preventable causes of mental retardation and developmental delay. Only through top notch research can we hope to find ways to prevent or manage it.
Gideon Koren, MD, FACMT, FRCPC
Director, The Motherisk Program
The Alcohol and Substance Use Helpline Update
Who is calling and what are they asking?
Q: I am pregnant and past my first trimester. Is it okay for me to drink
Q: I am breastfeeding my newborn and like to have wine with my dinner.
Q: I didnít know that I was pregnant when I went to a party last week. I drank more than I usually would and now Iím worried about fetal alcohol syndrome.
What are the risks to my baby?
The Alcohol and Substance Use Helpline has answered these and hundreds of similar questions. Operating daily from 9:00 a.m. to 5:00 p.m. in each of Canadaís time zones, the Motherisk Helpline hears from physicians, other health professionals and women throughout Canada. Whenever possible, callers are referred to treatment and support services in their home communities. Helpline counsellors also arrange for FAS assessment at The Hospital for Sick Children. The objective is to deliver evidence-based information to every caller and provide access to follow-up services.
Calls to the toll-free Helpline have increased steadily since its inception in 1998. As of July 28, 2000 Motherisk counsellors have received over 7900 calls related to alcohol and the use of cigarettes, cocaine, ecstasy and similar substances during pregnancy and while breastfeeding. (1) This represents approximately 22% of all calls to Motherisk in the same time period.
Most of the calls are from women themselves, rather than from their healthcare providers. The women range in age from 15 to 35 and older, and call Motherisk from all 10 provinces, the Territories and the United States. Still best known here in Ontario, the vast number of the calls are from within Ontario, with Alberta, British Columbia, and Quebec in second, third and fourth places, respectively.
Alcohol related calls constitute the second largest number of inquiries following calls about the effects of nicotine. Other commom questions include those about marijuana, cocaine and ecstasy use. The reason that nicotine arises so frequently is because there is a correlation between smoking and the use of alcohol and other recreational drugs. For example, a call concerning the use of cocaine is likely to also reveal the use of nicotine, but not necessarily alcohol. Also, women who drink socially may find it easier to discontinue drinking, while women who smoke may find it harder to overcome the underlying dependence.
In order to raise awareness of the service among healthcare workers and physicians, Motherisk staff has traveled to regional meetings of the College of Family Physicians throughout Canada. An increase of 45% in clinician calls and referrals over the past 6 months may be attributable to this targeted promotional effort.
The Motherisk Alcohol and Substance Use Helpline counsels hundreds of women each month on the risk of exposure to alcohol and other substances during pregnancy and while breastfeeding. Each conversation aims to meet individual needs. As a result, the length of calls can range from 10 minutes to one hour, depending on the variety of issues presented. Whenever possible, callers are linked to support services and followed up to monitor their situations. There is every indication that the demand for this sort of timely and authoritative counselling will continue to rise. Our goal - to ensure that those who need help will have reliable access to information and support. The Alcohol and Substance Use Helpline is supported by the Brewers Association of Canada.
E. Ho, Motherisk counsellor
Additional support for the Alcohol Helpline is provided by a grant under Health Canadaís Population Health Fund. The views expressed herein do not necessarily represent the official policy of Health Canada.
Neurodevelopment of children exposed in Utero to maternal binge alcohol consumption - a prospective, controlled study
Binge drinking, defined as a minimum of 5 drinks per single occasion, is a common form of alcohol consumption among North American women. Thirty-seven percent of pregnant teens and 24 percent of other pregnant women have reported drinking more than 5 drinks per single occasion in the first trimester of pregnancy (1,2) . Epidemiological data has shown an increased prevalence of binge drinking in pregnant women from 0.7 percent in 1991 to 2.9 percent in 1995.(3) The objectives of the Motherisk binge drinking study were to assess the fetal risk of maternal binge drinking during early pregnancy and to evaluate the specific effects of binge frequency. Our aim was to compare neurodevelopment of children exposed to maternal binge drinking in utero with children not exposed to known human teratogens.
The Women Included In The Study
The study group was comprised of women who called Motherisk about a binge drinking episode that occurred before they knew they were pregnant. A unique aspect of this prospective study is that the majority of the women in the study group remembered the exact time and number of binge drinking events.
The number of binges reported ranged from 1 to 20 episodes. Sixty-seven percent of women reported 1 to 3 binges with 5 to 6 drinks per binge. Eight percent reported 4 to 5 binges. Twenty-five percent reported more than six binges, with 5 to 7 drinks per binge. Ninety-one percent of women stopped drinking between 5 and 9 weeks of gestation, while 4 women continued drinking up to 12 weeks.
The mothers were assessed for IQ, as well as socio-economic status (SES), and were asked to answer a questionnaire about family function. To reduce the significance of confounders, mothers in the study group were matched to the comparison group for age, IQ, SES and number of cigarettes smoked. The mothers from the study group were not significantly different from the comparison group with regard to these matching criteria.
The study and comparison groups each included 51 children and their mothers. Children were included if their mothers reported binge drinking in the first trimester of pregnancy. Children were excluded if their mothers were heavy drinkers, or drank between binging events, or the child was exposed to known teratogens or other conditions that would adversely affect fetal outcome.
Before pregnancy outcome was known we collected information about maternal lifestyle, medical and obstetric history. A postnatal assessment including maternal and perinatal history, as well as the child's milestones, was first performed when the child was 6 to 9 months old. When the children reached the age of approximately 17 months or older they were assessed with a wide range of age appropriate neurobehavioral tests.
Neurodevelopment of children up to 36 months of age (n=26) was assessed with the Bayley Scales of Infant Development ñ II, childrenís cognitive abilities were tested with McCarthy Scales of Childrenís Ability (3 to 7 years of age, n=22), and the Wechsler Intelligence Scale III (n=3) was applied to the older children. The childrenís language was assessed with Reynell Developmental Language Scales.
Comparison statistics were followed by correlation and multivariate analysis. The children exposed in utero to maternal binge drinking were not different from the children of the matched comparison group in their age and physical characteristics. Nor did the study and control children differ with regard to Global IQ and Reynell language tests.
We also analyzed the neurobehavioral outcome with regard to the number of binges, number of drinks per binge and alcohol index, and again found no effect on cognitive abilities. Furthermore, when we performed regression analysis using maternal IQ, SES, parent stress measure, gestation age (GA), and maternal drinking as independent variables, we found that the childrenís cognitive outcomes were not affected by any of these independent variables.
Differences did arise, however, with regard to three out of nine temperament scales. Children exposed to more than six binges were rated higher in approach, adaptability and distractibility. Table 1
Approach scores were significantly higher among the study group children, indicating that these children were more disinhibited. Our findings showed that the number of binges, as well as the number of drinks per binge and alcohol index were significant predictors of outgoing behavior. The children of women who engaged in more binges were more willing to approach the unfamiliar. A similar pattern was observed for adaptability with maternal stress also accounting for a substantial proportion of the variance, reflecting poorer adaptability. We also found that maternal stress contributed significantly to distractibility. Table 2
We concluded that maternal binge drinking in early gestation affects preschool and school age childrenís behavior to a greater degree than cognitive function. Temperament is a more sensitive measure of a childís behavior than cognitive measures. Greater disinhibition may be a risk for future psychopathology and behavioral problems.
I. Nulman, D. Kennedy. J. Rovet, et al
Specific Temperament Test Items Characterizing (>90% cases) Elevated Scores in High Binge Group
Outgoing and adventurous
Table 2: Multiple Regression Predicting Behavioral Outcomes
| 95% Confidence
Interval for B
|Number of Binges||1.5||.50||.30||3.03||.003||.52||2.49|
|Number of Binges||1.69||.49||.36||3.48||.001||.74||2.66|
|Number of Binges||0.54||0.47||0.12||1.13||0.260||-0.41||1.48|
- Stratton K, Howe C, Battaglia F, eds. (1996) Institute of medicine summary: Fetal Alcohol Syndrome. Washington, DC: National Academy Press.
- Eckardt MJ, File SE, Gessa GL, Grant KA, Guerri CG, Hoffman PL, Kalant Koob GF, Li TK,Tabakoff B (1998). Effects of Moderate Alcohol Consumption on the Central Nervous System. Alcoholism: Clinical and Experimental Research, 22 (5): 998 - 1040.
- Ebrahim SH, Diekman ST, Floyd RL, and Decuofle P (1999)Comparison of binge drinking among pregnant and non pregnant women, United States, 1991- 1995. American Journal of Obstetrics and Gynecology;180(1): 1 - 7.
Streissguth AP, Barr HM, Sampson PD, Bookstein FL, Darby BL (1989)Nerobehavioral Effects of Prenatal Alcohol: Part I. Research Strategy. Neurotoxicol Teratol;11:461-476.
Sampson PD, Streissguth AP, Barr HM, Bookstein FL (1989) Neurobehavioral Effects of Prenatal Alcohol: Part II. Partial Least Squares Analysis. Neurotoxicol Teratol;11:477-491.
BouthiusDJ, Goodlett CR, West JR (1988) Blood alcohol concentration and severity of microencephaly in neonatal rats depend on the pattern of alcohol administration. Alcohol; 5: 209 -14.
Clarren SK, Bowden DM (1982) Fetal alcohol syndrome: a new primate model for binge drinking and its relevance to human ethanol teratogenesis. J Pediatr; 101:819-24.
Clarren SK, Astley SJ, Gunderson VM, Spellman D (1992) Cognitive and behavioral deficits in nonhuman primates associated with very early embryonic binge exposures to ethanol. J Pediatr; 121:789-96.
Tolo K, Little RE (1993) Occasional Binges by Moderate Drinkers: Implications for Birth Outcomes. Epidemiology; 4:415-420.
MECONIUM TESTING FOR FAEEA Biomarker for In Utero Exposure to Ethanol
Alcohol is the most widely used human teratogen, yet the biochemical mechanism of teratogenesis is not known (1). Fetal alcohol syndrome (FAS) is the most severe of fetal alcohol related abnormalities which may be seen in the children of women who drink heavily throughout pregnancy (2). It is also the leading cause of mental retardation.
As with any other drugs of abuse, the ascertainment of gestational exposure to alcohol is critical to the diagnosis of fetal alcohol related abnormalities.The most common methods for detection of alcohol use rely on maternal reports. However, it is widely recognized that maternal reports are likely to underestimate the true amount of alcohol consumed.
The easiest way to identify alcohol use is to measure it in blood, breath or urine, but this simple test cannot distinguish between acute and chronic alcohol consumption. Moreover, it has been shown not to detect "second hand drinking" by the fetus.
In order to establish a diagnosis of fetal alcohol related abnormalities, in utero exposure to ethanol is best established by an objective biological marker for alcohol or alcohol metabolites, such as acetaldehyde "seen" by the fetus. Stoler et al used a combination of 4 maternal blood markers of alcohol use in detecting alcohol-abusing pregnant women, yet many cases were missed. (3) A direct test in the newborn would potentially yield more direct information about the magnitude of true gestational exposure to alcohol which in turn, could be used in the clinical diagnosis of the child. Yet until recently there has been no objective biological marker for the detection of long term in utero exposure to alcohol.
Motheriskís search for that objective bio-marker is based in part on studies in adult drinkers showing that circulating ethanol is transesterified with fatty acids to produce fatty acid ethyl esters (FAEE). Other recent studies have identified FAEE in meconium (4). Presently it is not known whether FAEE are formed mostly in the mother and cross the placenta or whether they are formed in the fetus as well. Bearer et al have shown that the placenta has the necessary enzyme to produce these alcohol metabolites (5). Our in vitro studies provide the first evidence that transesterification of ethanol and fatty acids can occur in the meconium itself.
We are now embarking on a large epidemiological study which will be instrumental in evaluating the maternal-fetal pharmacokinetics of FAEE, and the relationship between the patterns and amounts of alcohol consumed by the pregnant mother and the accumulation of FAEE in meconium.
If confirmed by large studies, FAEE may become the first neonatal biological marker for babies at risk for alcohol-related birth defects.
J. Klein, MSc
- Koren G, and Nulman I.Teratogenic drugs and chemicals in humans. In : Maternal- Fetal Toxicology. Ed. Koren G. Publisher:Marcel Dekker, New York 1994. 33-48.
- Nulman I, Gladstone J, O'Hayon B. Koren G.The effects of alcohol on the fetal brain. Handbook of Developmental Neurotoxicology 1998; 567-586.
- Stoler JM, Huntington KS, Peterson CM, Peterson KP, Daniel P, Aboagye KK, Lieberman E, Ryan L, Holmes L.B. The prenatal detection of significant alcohol exposure with maternal blood markers. J Pediatr 1998; 133, 346-352.
- Bearer CF, Moore C, Salvatore AE, Lee SC, Buck KJ, Singer L. Meconium FAEE: Development of a biological marker. Alcohol Clin Exp Res 1998; 22(3), 103 A.
- Bearer CF, Gould S, Emerson R, Kinnunen P, Cook CS. Fetal Alcohol Syndrome and Fatty Acid Ethyl Esters. Pediatr Res 1992;31; 492-495.
THE ROLE OF ACETALDEHYDE
A Potential Mechanism For Fetal Alcohol Syndrome
In 1973 Jones and Smith1 put a name to the deleterious effects of alcohol on the developing embryo/fetus and coined the term Fetal Alcohol Syndrome (FAS). Since then researchers have sought to understand the mechanism leading to the fetotoxic effects of maternal alcohol consumption. A number of mechanisms have been proposed and possible contributions from more than one pathway suggests that alcohol related birth defects (ARBD) may be a multifactorial manifestation. The relative contribution of ethanol and its first proximate metabolite, acetaldehyde (AcH), to the teratogenesis still is not known, but both have been illustrated to be teratogens in animals (2-5).
We know that blood alcohol concentration-time curves do not differ significantly betweenalcoholics and non-alcoholics. (6,7) In contrast, AcH levels may be variable and elevated in some alcoholics (8-11). Some studies have been done to suggest that women who give birth to children with ARBD have a trend towards higher AcH levels (12,13). The high degree of variability in the clinical presentation of ARBD (only about 4 % of alcoholic women produce children with FAS), may be explained by the high degree of variability of AcH levels found in alcoholics, as compared to low variability of ethanol concentrations. It may be then, that alcoholics who produce high AcH levels are at risk of having an affected child (14).
We also know that the characteristic facial features present in those affected with the full-blown syndrome are not unique to FAS. The presence of epicanthic folds, wide nasal bridge, short nose, undefined philtrum, and thin upper lip are also characteristic of pyruvate dehydrogenase (PDH) deficiency. PDH deficiency is a mitochondrial disorder affecting energy metabolism (15). The impaired ability to convert pyruvate to acetyl coenzyme A (CoA) that occurs in PDH deficiency results in secondary lactic acidosis and thus has a significant effect on fetal development. Because of the similarities in the facial anomalies characteristic of FAS and PDH deficiency, and the variability of AcH levels among alcoholics, we have hypothesized that impairment of PDH occurs in the presence of AcH and contributes to the pathogenesis of ARBD.
We have conducted kinetic experiments with purified porcine heart PDH and showed that AcH inhibits PDH. Parallel studies using ethanol instead of AcH as the potential inhibitor showed no inhibition. Purified PDH complex incubated with [1,2-(14) C]-AcH formed covalent adducts with proteins in the complex, but such covalent binding was non-contributory to the observed inhibition. Our results show that AcH impairs the activity of PDH. Since PDH levels are low throughout development and do not reach adult levels until the fetus reaches term, even a small degree of inhibition may have severe effects (16).
Work is currently in progress to document the effects of AcH on PDH in the fetal rat.
Brian H. Robinson
- Jones KL, Smith DW, Ulleland CN,Streissguth AP (1973) Pattern of malformation in offspring of chronic alcoholic mothers. Lancet i: 1267-1271.
- Ukita K, Fukui Y, Shiuta K (1993) Effects of prenatal alcohol exposure in mice: influence of an ADH inhibitor and chronic inhalation study. Reproductive Tox 7: 273-81.
- Ali F, Persaud TVN (1988) Mechanisms of fetal alcohol effects: role of acetaldehyde. Exp Pathol 33: 17-21.
- Hillbomm ME, Srviharju MS, Lindros KO (1983) Potentiation of ethanol toxicity by cyanamide in relation to acetaldehyde accumulation. Toxicol Appl Pharmacol 70: 133-139.
- Sreenathan RN, Padmanabhan R, Singh S (1982) Teratogenic effects of acetaldehyde in the rat. Drug Alcohol Depend 9: 339-350.
- DiPadova C, Worner TM, Lieber CS (1987) Effect of abstinence on the blood acetaldehyde response to a test dose of alcohol in alcoholics. Alcohol Clin Exp Res11: 559-561.
- Palmer KR, Jenkins WJ (1982) Impaired acetaldehyde oxidation in alcoholics. Gut 23: 729-733.
- PanÈs J, Caballeria J, Guitart R, ParÈs A, Soler X, Rodamians M, Navasa M, ParÈs X, Bosch J, RodÈs J (1992) Determinants of thanol and acetaldehyde metabolism in chronic alcoholics. Alcohol Clin Exp Res 17: 48-53.
- Adachi J, Mizoi Y, Fukunanga T, Ogawa Y, Imamichi H (1989) Comparative study on ethanol elimination and blood acetaldehyde between alcoholics and control subjects.
- Nuutinen H, Lindros KO, Salaspuro M (1983) Determinants of blood acetaldehyde level during ethanol oxidation in chronic alcoholics. Alcohol Clin Exp Res7: 163-168.
- Lindros KI, Stowell A, Pkkarainen P, Salaspuro (1980) Elevated blood acetaldehyde in alcoholics with accelerated ethanol elimination. Pharmacol Biochem Behav (Suppl. 1) 13: 119-124.
- VÈghelyi PV, Osztovics M, Kardos G, Leisztner L, Szaszovszky E Igali S, Imrei J (1978) The fetal alcohol syndrome: symptoms and pathogenesis. Acta Paediat Acad Sci Hung 19: 171-189.
- Niemela O, Halmesmaki E,Ylikorkala O (1991) Hemoglobin-acetaldehyde adducts are elevated in women carrying alcohol-damaged fetuses. Alcohol Clin Exp Res 15:1007-1010.
- Abel EL (1995) An update on incidence of FAS: FAS is not an equal opportunity birth defect. Nerotox Teratol 17: 437-443.
- Robinson BH (1995) Mitochondrial defects: An overview of inborn errors associated with lacticacidemia. Int Pediatr 10: 82-88.
- Robinson BH, Sherwood WG, Oei J (1977)The development of pyruvate dehydrogenase in the subhuman primate Macaca mulatta. Biol Neonate 32: 154-157.
FAS RESEARCH ROUNDTABLE ABSTRACTS
On September 8, 2000 Motherisk will host the Fetal Alcohol Syndrome Research Roundtable at The Hospital for Sick Children where Canadian clinical and experimental researchers will present their latest findings. It will be a day-long discussion of the markers, mechanisms, and biologic effects of FAS, as well as evidence-based research concerning FAS prevention, diagnosis and intervention.The articles in this issue of the Motherisk Newsletter, along with the following abstracts, describe much of the research to be discussed at the September 8th Roundtable.
ALCOHOL RELATED NEURODEVELOPMENT DISORDER (ARND ) -
A UNIQUE PROFILE OF DEFICITS AND ASSETS
R. Greenbaum, B.Sc., D.C.S.
I. Nulman, M.D.
J. Rovet, Ph.D.
G. Koren, M.D., F.R.C.P.(C)
Alcohol Related Neurodevelopmental Disorder (ARND) describes children whose neuropsychological development has been adversely affected by prenatal alcohol exposure, and includes children who do not meet all the diagnostic criteria for FAS. A major problem in diagnosing these children is that the clinical phenotype of ARND without physical dysmorphology has not been well-defined. This work represents the first systematic clinical report on diagnosing ARND in Canada.
Fifty-two children aged 4-18 years were referred to a hospital-based outpatient program in Toronto for a diagnostic assessment related to their prenatal alcohol exposure. We first used widely accepted clinical methods which were not pathognomonic. Subsequently, we took a novel approach by hypothesizing a neuropsychological profile of assets and deficits which better characterized the effects of prenatal alcohol exposure. We next determined the extent to which each child's individual neuropsychological profile was consistent with the proposed ARND profile. Statistical comparisons were made between those children fitting the ARND profile and those who did not in order to clarify which neuropsychological characteristics most significantly differentiated the two groups.
Fifty-seven percent (28 of 52) of the children who fulfilled our criteria were assigned to the ARND group while the remainder were assigned to the non-ARND group. While the two groups did not differ in physical presentation, children in the ARND group were more likely to have repeated a grade and received special education. They differed significantly from non-ARND children on standardized measures of intelligence, language, and memory abilities.
Statistical differences were not found on indices of attention and socioemotional problems, however, both groups presented with clinically significant elevations in these domains. Our findings suggest that future research will need to clarify the extent to which such problems are unique to children with ARND, particularly in contrast to other similar clinic-referred samples.
ADULT OUTCOME IN FAS : EDUCATION, EMPLOYMENT AND ATTENTION
Nanson, S. Brock
University of Saskatchewan
Saskatoon, Saskatchewan S7N 5A5
The first individuals diagnosed with fetal alcohol syndrome in the 1970ís are now reaching adulthood, yet there has been very little information available on adult outcome in this disorder. This study presents the first neuropsychological data on adults with FAS that has employed a carefully matched control group. One of the most enduring findings in younger children with FAS is difficulty with attention. Mirskyís model of attention provides a rich method for assessing these deficits with attention. It is composed of three elements: focus; sustain-vigilance; and shift. More recently a fourth element, encode, was added to the model.
Subjects in this study, 17 young adults with FAS (mean age 21.4 years) were compared to age, sex and IQ matched controls, who had no history of teratogenic exposure.
Each subject completed an interview outlining their status and a battery of neuropsychological tests. Only the results of the demographic and attention measures are presented here. Attention was assessed using the Talland Letter Cancellation Test (TLCT), a computerized version of the Continuous Performance Test (CPT), the Wisconsin Card Sorting Task (WCST), and the Arithmetic subtest of the Wechsler Adult Intelligence Scale-Revised. IQ was assessed using the Wechsler Adult Intelligence Scale - Revised (WAIS-R).
Intelligence: The mean IQ in the FAS group was 73.5. The mean IQ of the matched controls was 73.1. Employment and living arrangements: FAS adults were more likely to be living in the parental home than were controls. Educational achievements: FAS adults had lower educational achievements than controls. Attention: Adults with FAS had significantly more problems with sustaining attention within tasks, with shifting attention across tasks, and with encoding material into working memory, but did not differ from controls in terms of focusing attention. Young adults with FAS do appear to differ in subtle ways from other adults with developmental disabilities.
ETHANOL TERATOGENESIS INVOLVING THE DEVELOPING BRAIN
F. Brien, Ph.D.,
Department of Pharmacology and Toxicology,
Faculty of Health Sciences
Queenís University, Kingston, ON K7L 3N6
Maternal consumption of alcoholic beverages during pregnancy can produce a broad spectrum of dose-dependent toxic effects in the embryoñfetus, ranging from lethality or teratogenicity (birth defects) for chronic, high-dose use of ethanol through to suppression of fetal breathing-like movements for acute, low-dose use of ethanol. Fetal alcohol syndrome (FAS) is a human manifestation of ethanol teratogenesis (production of birth defects) that is diagnosed after birth during postnatal life. The most debilitating feature of FAS appears to be structural damage and functional changes of the developing brain that can have lifelong adverse intellectual, neurological and behavioral consequences (ethanol neurobehavioral teratogenesis).
Experimental animal investigations have demonstrated that one of the main target sites of ethanol neurobehavioral teratogenesis is the hippocampus of the developing brain. The hippocampus appears to play a major role in the processes of learning and memory, and in behavioral regulation. The mental deficiency and hyperactivity in patients with FAS may be due, at least in part, to injury to the hippocampus produced by prenatal exposure to ethanol.
In this study, a proposed mechanism for ethanol neurobehavioral teratogenesis involving the hippocampus will be assessed. This proposed mechanism is based on a signaling pathway that is involved in cell-to-cell communication and utilizes glutamate, a neuroactive amino acid. Glutamate interacts with a specific biochemical receptor molecule, the N-methyl-D-aspartate (NMDA) receptor, which regulates the activity of an enzyme, nitric oxide synthase (NOS) that synthesizes nitric oxide (NO), an important brain messenger molecule. It is postulated that suppression of the glutamateñ NMDA receptorñNOS signaling pathway in the fetus by chronic maternal consumption of ethanol plays a key role in causing structural and functional changes in the hippocampus. These changes manifest in postnatal life. This mechanism is supported by our investigations in the guinea pig.
In view of the apparent time course for loss of particular neurons in the hippocampus produced by chronic prenatal ethanol exposure that manifests in early postnatal life, it is proposed that therapeutic intervention, which targets the glutamateñNMDA receptorñNOS pathway, may lessen the magnitude of hippocampal injury that could manifest postnatally as adverse neurobehavioral changes. This research is supported by the Canadian Institutes of Health Research.
Karen A. Kimura, James N. Reynolds, and James F. Brien. Ethanol neurobehavioral teratogenesis and the role of the hippocampal glutamateñ N-methyl -D-aspartate receptorñnitric oxide synthase system. Neurotoxicology and Teratology, 22, in press (2000).
THE ASSOCIATION BETWEEN PATERNAL ALCOHOL EXPOSURE AND TURNER SYNDROME (TS ): PRELIMINARY RESULTS OF A HEALTH AND LIFE STYLE SURVEY OF PARENTS OF CHILDREN WITH TS
Kagan, S.Vohra, G. Koren, P. Selby
The Hospital For Sick Children
Toronto, Ontario, Canada.
Turner Syndrome is a sex chromosome aneuploidy that occurs as a result of a nondisjunctional error in meiosis I or anaphase lag; however, the etiology of this disorder remains unknown. Anecdotal evidence suggests that paternal alcoholism may play an unidentified role in the etiology of Turner syndrome (TS). Accordingly, the objectives of this study were: (1) to determine the potential association between paternal alcohol exposure and TS; and (2) to determine the potential association between selected health and lifestyle behaviors of the parents and TS.
This descriptive study employed a self-report survey methodology. The questionnaire was designed to solicit information about the parentsí health and lifestyle habits occurring one year prior to and throughout the pregnancy of their daughter with TS. The primary outcome measure included in the questionnaire was the Brief Michigan Alcohol Screening Test (BMAST). The remainder of the questionnaire included questions about 5 other health and lifestyle behaviors that were determined by clinical experts to be relevant to the objectives of this study. (i.e. medical history, allergies medications/drugs, nutrition smoking, alcohol consumption and environmental hazards.)
The study population was solicited from the Turnerís Syndrome Society of Canada and included any parent(s) having a child with TS who was of any age. The children were not karyotyped for this investigation, and hence this poses some limitation in interpreting the findings.
The questionnaires were mailed to 245 families and 212 families completed and returned the survey. This provided a response rate of 86.5%. Six of the fathers (3.6% n=166) and six of the mothers (3.6% n=165) had scores of 5 or more on the BMAST (scores of 5+ are considered to be in the "alcoholic range").This is considerably lower than the population norm of 9.5%. An interesting finding suggested that 54% of the fathers and 36% of the mothers reported that they had been exposed to two or more environmental hazards.
Our study has not indicated that
there is a potential association between paternal or maternal alcohol
consumption and TS. However, we were surprised to learn that a previously
unidentified association between exposure to environmental hazards and
TS may exist. This hypothesis requires further investigation.
MOTHERISK SEEKS STUDY PARTICIPANTS
Asthma Medications In Pregnancy Project
Motherisk is currently collaborating on a study to investigate the effects of asthma and its treatment on pregnancy outcome. Eligible subjects include women, less than 20 weeks pregnant, who are diagnosed with asthma which requires treatment. Healthy women, less than 20 weeks pregnant, who are not on any chronic therapies and not exposed to any teratogenic drugs qualify as controls. Participation will involve 3-4 telephone interviews with the mother during pregnancy and 1 after delivery. Participants will also be asked to consent to the release of their medical records pertaining to delivery and infant's health.
Rheumatoid Arthritis & Arava (Leflunomide)In
Motherisk is also collaborating on a study to investigate the effects of Arava (leflunomide) on pregnancy outcome. Any woman treated for rheumatoid arthritis who has taken leflunomide or other medications and who is less than 20 weeks pregnant, can participate. Women will be interviewed by phone 2-3 times in the pregnancy and again after delivery. In addition, the child will be examined by a pediatrician after birth. For information about these Motherisk studies please contact Dr. Costei at 416-814-7654 ext 4467 or speak to a Motherisk counsellor (416-813-6780).
BREAKING THE CYCLE - INTEGRATED SERVICES FOR PREGNANT AND PARENTING WOMEN AND THEIR CHILDREN
Since 1995 Breaking the Cycle (BTC) has helped women who are pregnant and/or parenting children under 6 years of age, and are struggling with problems related to alcohol and substance use. But what makes BTC truly unique is that it also helps their young children whose physical and psychosocial health and well-being are at risk because of their exposure to alcohol and drugs.
Through the efforts of six partner agencies - Mothercraft, Jean Tweed Centre, Motherisk, Childrenís Aid Society of Toronto, Catholic Childrenís Aid Society, Toronto Department of Public Health, and with funding from Health Canadaís Community Action Program for Children (CAPC), this single access, community-based model provides a wide range of adult and child services at one site in downtown Toronto.
An awareness education and outreach strategy engages women in the earliest stages of their pregnancy, to reduce the biological, psychosocial and cumulative risks of alcohol and drug use to the fetus and provide prenatal care and birth planning support. With time and acceptance, even the most high-risk woman can be engaged in a process of planning for her infant.
The BTC Target Population
BTC has provided services to almost 500 families. An average of 100 new families are admitted each year. Ninety-two (92%) of the women admitted are parenting at admission; 25% are pregnant.
All of the BTC children are, or have been, exposed to substances or substance-using environments. Forty-six percent (46%) of BTC mothers have reported that their primary addition is to crack cocaine, 34% have reported that their primary addiction is to alcohol. The average length of their addiction is 11 years. Sixty-three percent (63%) of BTC mothers have reported that they used their primary drug of choice within the last 4 months prior to attending BTC. Many are still using their drug of choice at admission to BTC.
Half (50%) of BTC women have reported that they received the services of a child welfare agency when they were children, indicating an inter-generational pattern of maltreatment. One third of BTC mothers had at least one child in foster care at admission. Approximately 90% of BTC families also receive the services of a child welfare agency. Almost 75% of BTC mothers are single, separated, divorced or widowed and are parenting an average of 2 children each. Eighty-five percent (85%) of BTC mothers have report that their annual income is less than $14,999, with 43% reporting that their income is less than $9,999 per year. Twenty-four percent (24%) of BTC mothers report that they have no fixed address, and/or are living in transient or sub-standard housing situations.
Sixty-seven percent (67%) of BTC mothers have reported a history of sexual abuse, 80% reported a history of physical abuse and 83% reported a history of emotional abuse. Forty-two percent (42%) of BTC women have reported that they had attempted suicide, with an average of 2.5 attempts. Twenty-seven percent (27%) have reported that they had engaged in self-harm behaviors. Two-thirds (66%) reported a family history of substance use, indicating an inter-generational cycle of substance use. These data confirm that BTC is reaching and engaging a very high-risk and marginalized population of women and children. They are also the first Canadian data that describe the characteristics and needs of this vulnerable population in a Canadian context.
Child Health And Functioning
Approximately 25% of the women at BTC are pregnant at admission. The children born after their families were admitted to BTC had fewer birth complications and decreased postnatal diagnoses than those of the same mothers who were born before their families were admitted to BTC. In addition, BTC-born children had better maternal health ratings, fewer health concerns, fewer separations from their mothers and mothers had fewer developmental concerns about their children.
Developmental ratings of BTC-born children showed significant improvement over a six-month period in which the family was involved in the program. The developmental lag, which is often reported in the research on substance-exposed children, did not materialize.
Pre-and post measures of maternal stress, dysfunction and distress indicated that over a six-month period in which they attended BTC, mothers experienced less parental distress, less dysfunctional parent-child interactions, and less stress due to a difficult child. These measures were gathered using a semi-structured interview that was created for program evaluation by Boyle and Offord (1995). Mothers also reported less use of harsh discipline, more mother-child activities, and increased positive feelings about parenting since attending BTC.
Maternal Health And Substance
Women who attend BTC access health and counselling services to meet their own needs and the needs of the child(ren). At this time, the results of measures to evaluate maternal substance use are inconclusive. However, both BTC staff and client focus groups reported that many mothers have been able to make significant and difficult changes in their substance-using lifestyles and are on the road to improved maternal health.
The continuing challenge is effective outreach and client engagement. That is why BTC conducted a recent study entitled Drug Addiction & Pregnant/Parenting Women: Factors Affecting Client Engagement. An important finding was that women who present for service at BTC while pregnant are significantly more likely to be homeless, use crack cocaine as their drug of choice, and have attained a lower level of education than non-pregnant women. These factors were identified as significant barriers to engagement of pregnant, substance-using women in programs, and to treatment maintenance.
This population of homeless, pregnant women represents a higher-risk sub-population of drug-using women whose barriers to health and effective treatment are even greater than within the larger population of substance-using pregnant or parenting women. BTC has therefore launched a pilot project to reach these women through street-based agencies in Toronto that serve homeless women. Agency staff have responded enthusiastically, helping to refer pregnant women to withdrawal management services, medical care, prenatal support services, and BTC. Additional homeless pregnant women have also been identified through women attending these street-based agency programs.
FAS Diagnostic Clinic
Another important initiative is the BTC/Motherisk community-based FAS Diagnostic Clinic at Breaking the Cycle. This Clinic will extend the expertise of the Motherisk FAS Clinic to the community. Motheriskís medical/diagnostic expertise will complement the history-taking and developmental assessments that currently take place at BTC, and will complete the assessment and possible diagnosis of children who are affected by their motherís prenatal alcohol use.
Early diagnosis of children who are effected will help ensure appropriate programming, education and support to children and families in the preschool and school years, and may prevent the development of many of the secondary disabilities associated with prenatal alcohol exposure. Families and children will receive comprehensive pre-diagnostic and post-diagnostic supports as they undergo this assessment process. For more information about this or other BTC services please call (416) 364-7373.
BTC Program Manager
The Alcohol and Substance Use Helpline is sponsored by the Brewers Association of Canada.
This issue of the Motherisk Newsletter is supported by the Brewers Association of Canada.