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Current Studies at Motherisk
Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
Diclegis Surveillance Program Study
Diclectin Surveillance Program Study
Study seeks women between 4 and 12 weeks in their pregnancy with morning sickness (NVP)
Pregnancy in Women with Multiple Sclerosis
Environmental Exposures and Children's Health
Alcohol Use during Pregnancy
Control of Hypertension in Pregnancy Study
Folic Acid Before and During Pregnancy
Lamisil in Pregnancy
Meridia in Pregnancy
Autoimmune Diseases in Pregnancy Project
Motherisk Newsletters: Spring 1999, No. 10Spring 1999, No. 10
The Motherisk Alcohol and Substance Use Helpline, 1-877-FAS-INFO was established in November, 1998. This new service, sponsored by the Brewers Association of Canada, is helping pregnant women, healthcare providers, social workers and adoptive parents understand the fetal risks of alcohol, smoking and drugs of abuse.
An important feature of the program is a systematic effort to collaborate with and learn from other Canadian researchers. The following study was conducted by a leading group of Canadian researchers at the University of British Columbia.
Identification by primary care physicians of "at risk" drinking during pregnancy - A population based study
Researchers estimate that 10-20% of all mental retardation is caused by alcohol misuse/ abuse during pregnancy ( 1 ). This is a preventable problem and is one of the most important public health issues facing our society today. Identification of women who are at risk of alcohol misuse and abuse remains a difficult issue. While a number of screening devices are available to assist health professionals in identifying these women, routine screening is frequently not done.
Two short screening tests have been proposed. The first, CAGE ( 2 ) is a 4-item questionnaire designed for use in primary care practices to identify individuals with alcohol problems. T-ACE is an adaptation of CAGE which drops one question and replaces it with a question on tolerance ( Table 1 ). It was specifically designed for use during pregnancy to increase the sensitivity of CAGE ( 3 ). It has good sensitivity and specificity but has not been used on a population basis.
In the present study, physicians in Vancouver Island were trained in the use of T-ACE as a clinical screening tool to identify women at risk for moderate to heavy alcohol use during pregnancy. Birth records for the 1-year period were accessed for all birth occurring within the study area. Finally, a random sample of 403 women also participated in structured lifestyle interviews.
The T-ACE questionnaire for problem drinking in women
The study population consisted of all women attending physicians for prenatal care and/or delivering their baby in hospitals within the 5 regional hospital districts of central and upper Vancouver Island during a 1 year period from July 1, 1990 to July 1, 1991. Information gathered during the course of the study has been divided into three main sources: MRDF, T-ACE, and HVIS.
MRDF -- (n=3659). Perinatal and newborn information as well as general demographic data were collected using the Medical Record Data Form (MRDF). The MRDF data were collected for all births that occurred within the study area between July 1, 1990 to July 1, 1991.
T-ACE -- (n=3228). Data concerning alcohol consumption were provided by physicians who were asked to complete a T-ACE questionnaire on each of their pregnant patients who were likely to give birth during the study period. For this reason, collection of the T-ACE data was begun prior to the beginning of the study period (April 1991) and extended beyond the end of the study (December 1991). The details of T-ACE are described in ( Table 1 ) ( 4 ).
HVIS -- (n=403). Home visits (HVIS) including structured lifestyle interviews were conducted by a research nurse with a sub-sample of the women who gave birth during the study period. Interviews took place between July 1990 and July 1991.
A total of 315 physicians practiced within the area during the study period. Of these, 208 (66%) completed at least one T-ACE questionnaire. Overall, T-ACE questionnaires were completed on 1721 (47%) of the 3659 women giving birth during the study period. T-ACE questionnaires were also completed for 1507 women who did not give birth during the study period.
Accuracy of T-ACE Application
For those women with two sets of T-ACE data, the correlation between the two sets of total scores (r=0.74) suggests that the questionnaire exhibits adequate test-retest reliability. Precise agreement was achieved on 111 of 192 (57.8%) cases. The vast majority of disagreements were based on scoring differences of just one point. A second measure of the accuracy of the T-ACE data can be derived from the alcohol consumption information gathered in the structured home interviews conducted with a random sample of 403 women. The correlation between the amount of alcohol women reported consuming, and their T-ACE score (r=.366, p<.0001) indicates significant agreement between the T-ACE score and the more detailed consumption history derived through the home interview.
At issue is whether or not the questionnaire was more likely to be completed from some types of women over others. T-ACE forms and structured home interviews were more likely to be completed for Caucasian women than for Native and East Asian women (p<.0001). Unemployed women were over-represented in the group of women with completed T-ACE forms, while homemakers were under-represented (p<.0001). In addition women with a completed T-ACE form made more visits for prenatal care (p<.0008), had heavier babies (p<.02), and spent reliably less time in hospital (p<.002) than those women with no T-ACE form completed.
T-ACE scores and markers of early alcohol use
High T-ACE scores were associated with an earlier onset of drinking, with the average "age of first drink" ranging downward from 15.6 years for those scoring 0 on T-ACE, to 13.5 years for women with scores of 5. Similarly, the age at which women reported first getting drunk, ranged from 17.0 years for those scoring 0 on T-ACE, down to 15.0 for those scoring 5 on T-ACE (p<.0001). There was also a significant correlation between the age of one's first drink and the age one reported first getting drunk (r=.67, p<.0001).
Demographic and Socio-Emotional Stressor Variables
Women in the Medium and High risk groups were, on average, younger than those in the Low risk group, (p<.0001) as were the fathers of their infants (p<.0001). Caucasian women were under-represented in the Medium and High risk groups, while Native women were over-represented (p<.0001). Married women were less likely to be categorized as High risk, while single and separated women and those living in common-law relationships were more likely to be at High risk (p<.0001). Women who reported being unemployed, or who listed no employment information whatsoever, were also more likely to fall in the High risk group (p<.0001).
T-ACE total scores were higher for those women reporting any kind of socio-emotional stressor (e.g., financial troubles, sexual or physical abuse, life stress, drug use) than for those who reported no such stressors (p<.003). A significant positive correlation was found between T-ACE total score and the absolute number of such stressors reported (r=.121, p<.02). T-ACE scores were higher among those reporting drug use within the family (F=8.7, p<.004), mental, physical, or sexual abuse (p<.04), general life stress (p<.05), and crime and other social stressors (p<.04).
T-ACE Risk and Birth Outcome
The gestational age of infants born to women in the High risk category was significantly lower than that of the other risk groups (p<.008). Significant differences were also found between the Low and High risk groups in terms of infant birth weight (p<.04), and head circumference (p<.03). The presence of meconium was associated with higher T-ACE scores (p<.03), as was the frequency of intubation immediately following birth (p<.04). Length of hospital stay also increased with T-ACE score (r=.053, p<.04). Finally, women in the High risk group made fewer visits for prenatal care than did those in the Low and Medium risk groups (p<.0001).
The results of this study indicate that the issues of surveillance are complex and that multiple strategies are likely to be needed if we are to reach the population of women who are potentially at risk. Physicians are an important component of this system and, as this study has shown, if they are committed, physicians can effectively survey the majority of the population. In addition, other strategies for surveillance need to be introduced. These strategies might include public health nursing, community health representatives on reserves, and specialized services such as Pregnancy Outreach Programs.
Robert W. Armstrong,
M.D., Ph.D., FRCPC
Christine A. Loock, MD
Geoffrey C. Robinson, MD
Norma Lupton, R.N,
Chris Lalonde, Ph.D.
Abel EL, Sokol RJ: Incidence of
fetal alcohol syndrome and economic impact of FAS related anomalies.
Drug Alcohol Depend 1987; 19:51-70.
Ewing JA: Detecting alcoholism, the CAGE questionnaire. JAMA 1984; 252: 1905-07.
Able EL, Sokol RJ: A Revised
Conservative Estimate of the Incidence of FAS and its
Economic Impact. Alcoholism: Clinical and Experimental Research
1991; 15: 514-524.
- Russell M: New assessment tools for risk drinking during pregnancy. Alcohol Health & Research World 1994; 18: 55-58.
Alberta and Prairie Province FAS
Initiative and the Alberta Medical
Association have just completed clinical practice guidelines for the
prevention and diagnosis of fetal alcohol syndrome. Another valuable
contribution to the prevention of FAS is the Community Action Guide
developed by the
British Columbia Ministry for Children and Families.
For more information call Motherisk toll-free at 1-877-FAS-INFO, or the Alberta Clinical Practice Guidelines Program, 1-800-272-9680, or BC Adult Addiction Services, (250) 953-3113.
PREGNANCY OUTCOME FOLLOWING MATERNAL ORGANIC SOLVENT EXPOSURE
Q : One of my patients is a laboratory technician who routinely handles organic solvents. She has just learned that she is pregnant and depends very much on this job as her husband is unemployed. What is the risk to her fetus?
Organic solvents are a structurally diverse group of low molecular weight liquids that are able to dissolve other organic substances. Chemicals in the solvent class include aliphatic, aromatic and halogenated hydrocarbons; aliphatic alcohols; glycols; and glycol ethers ( 1 ). Fuels are a mixture of various hydrocarbons. They are ubiquitous in industrialized society, both at work and at the home. They may be encountered as individual agents or in complex mixtures such as gasoline. Incidental exposures may include vapors from gasoline, lighter fluid, spot removers, aerosol sprays and paints. These short duration and low level exposures may often go undetected. More serious exposures occur mainly in the industrial or laboratory settings during manufacturing and processing operations such as dry cleaning, regular working with paint removers, thinners, floor and tile cleaners, glue and as laboratory reagents. Gasoline sniffing or glue sniffing, albeit not occurring in the occupational setting, is another source of exposure to organic solvents during pregnancy.
Counselling pregnant women who are occupationally exposed to numerous chemicals (mostly organic solvents) is problematic because it is difficult to estimate the predominant chemicals and their by-products. Even after identifying the more toxic agents, it is still difficult to assess the circumstances of exposure as for many chemicals one can measure neither airborne nor blood levels. Smelling the odour of organic solvents is not indicative of a significant exposure as the olfactory nerve can detect levels as low as several parts per million which are not necessarily associated with toxicity. As an example, the odour threshold of toluene is 0.8 parts per million whereas the TLV-TWA (threshold limit value-time weighted average) is 100 parts per million. In addition, reproductive information on many individual solvents is either limited to animal studies or nonexistent.
Many organic solvents are teratogenic and embryotoxic in laboratory animals depending on the specific solvent, dose, route of administration and particular animal species ( 1 ). The various malformations described include hydrocephaly, exencephaly, skeletal defects, cardiovascular abnormalities and blood changes. Also, some studies suggest poor fetal development and neurodevelopmental deficits. In a portion of these studies exposure levels were high enough to induce maternal toxicity.
Organic solvents are a diverse, complex group and because exposure usually involves more than one agent and different circumstances, adequate human epidemiological studies are difficult to interpret. Many studies are subject to recall and response bias and are not always controlled for other risk factors such as age, smoking, ethanol, and concurrent drug ingestion. It is difficult to prove or quantify the suspicion that organic solvents are a reproductive hazard. While fetal toxicity is biologically sensible in cases of intoxicated mothers, evidence of fetal damage from levels that are not toxic to the mother is scanty, inconsistent or missing.
The tool used by us to analyze the literature for an overall summary of risk between in utero inhalational exposure to organic solvents and adverse pregnancy outcome is meta-analysis. Motherisk conducted the first meta-analysis of pregnancy outcome following maternal organic solvent exposure aiming at two outcomes of interest: major malformations and spontaneous abortion ( 2 ). Included were studies that were case-control or cohort in design and indicated first trimester (or up to 20 weeks gestation for spontaneous abortion) maternal occupational solvent exposure.
Five studies were included in the malformation analysis ( 3-7 ). Study size of the studies ranged from 570 to 2950 patients. The overall summary odds ratio was 1.64 (95% CI: 1.16 - 2.30) which indicates that maternal inhalational occupational exposure to organic solvents is associated with an increased risk for major malformations.
Five studies were included in the spontaneous abortion analysis ( 8-12 ). Study size ranged from 57 to 1096 patients. The overall ORs of 1.25 (95% CI: 0.99-1.58) indicates that maternal inhalational occupational exposure to organic solvents is associated with a tendency towards a small increased risk for spontaneous abortion. The addition of one study of similar effect size would have rendered this trend statistically significant.
There are some considerations to bear in mind when interpreting results of the malformation and spontaneous abortion meta-analysis. Organic solvents belong to many classes of chemicals. Not all of the studies have examined the exact same groups of solvents in terms of both extent and range of solvents, as well as frequency and duration of exposure. Also, the malformations listed in each of the papers seem to reflect a diverse range of anomalies. One might expect to notice a particular trend in malformations between studies, however, this does not appear to be the case.
It is prudent to minimize women's exposure to organic solvents by ensuring appropriate ventilation systems and protective equipment. Each woman should be counselled about the risk of organic solvent exposure during pregnancy to allow her to make an informed decision as to the continuation of her work. If there are concerns about worksite exposure levels exceeding current occupational exposure limits, they must initially be discussed between the employee and supervisor, and if warranted, an external consultant should be hired to perform air testing.
A: Available epidemiologic data indicate your patient's fetus may have an increased risk for malformations. It is recommended that she minimize her occupational exposure to organic solvents by routinely using ventilation systems and protective equipment. This is most important during the first trimester of pregnancy.
Kristen I. McMartin, MSc
Gideon Koren, MD, FRCPC, FACCT
Schardein J: Industrial Solvents.
In Schardein J: "Chemically Induced Birth Defects." New York:
Marcel Dekker, 1985. pp 645-658.
McMartin KI, Chu M, Kopecky E,
Einarson TR, Koren G. Pregnancy outcome following maternal
organic solvent exposure: a meta-analysis of epidemiologic
studies. Am J Ind Med. 1998:34:288-292.
Axelsson G, Liutz C, Rylander R.
Exposure to solvents and outcome of pregnancy in university
laboratory employees. Br J Ind Med. 1984:41:305-312.
Tikkanen J, Heinonen O.
Cardiovascular malformations and organic solvent exposure
during pregnancy in Finland. Am J Ind Med. 1988:14:1-8.
Holmberg PC, Kurppa K, Riala R,
Rantala K, Kuosma E. Solvent exposure and birth defects: an
epidemiologic survey. Prog Clin Biol Res. 1986:220:179-185.
Cordier S, Ha MC, Ayme S, Goujard
J. Maternal occupational exposure and congenital
malformations. Scand J Work Environ Health. 1992:18:11-17.
Lemasters GK. An epidemiological
study of pregnant workers in the reinforced plastics industry
assessing outcomes associated with live births. Cincinnati
(Ohio). University of Cincinnati. 1983.
Windham GC, Shusterman D, Swan
SH, Fenster L, Eskenazi B. Exposure to organic solvents and
adverse pregnancy outcome. Am J Ind Med. 1991:20:241-259.
Lipscomb JA, Fenster L, Wrensch
M, Shusterman D, Swan S. Pregnancy outcomes in women
potentially exposed to occupational solvents and women working
in the electronics industry. J Occup Med. 1991:33:597-604.
Schenker MB, Gold EB, Beaumont
JJ, Eskenazi B, Hammond SK, Lasley BL et al. Final report to
the Semiconductor Industry Association. Epidemiologic study
of reproductive and other health effects among workers employed in the
manufacture of semiconductors. University of California at Davis. 1992.
Pinney SM. An epidemiological
study of spontaneous abortions and stillbirths on
semiconductor employees. Cincinnati (Ohio). University of Cincinnati.
- Eskenazi B, Bracken MB, Holford TR, Crady J. Exposure to organic solvents and hypertensive disorders of pregnancy. Am J Ind Med. 1988:14:177-188.
CONTINUING DRUG THERAPY WHILE BREASTFEEDING
Q: Some of my patients who need specific drugs during the postpartum period are hesitant to breastfeed even when I tell them that, according to available evidence, these drugs are safe. Am I right about this and how should I advise my patients?
With few exceptions, medications used by women postpartum are safe for suckling infants because very small amounts of the drugs get through to the baby. ( 1 ) Nursing women are often concerned, however, about their drugs having adverse effects on their infants, and this leads them to discontinue breastfeeding. We found that the less reassuring physicians were about the compatibility of a drug with breastfeeding, the higher the incidence of stopping breastfeeding. ( 2 ) The Motherisk Program is receiving increasing numbers of queries about maternal medications during breastfeeding. As part of follow up of mothers receiving chronic drug therapy, babies should be routinely monitored for signs or symptoms of ill effects.
In a recent Motherisk study,
we showed that epileptic women tended to breastfeed at about
half the rate of control subjects and to breastfeed for a
substantially shorter period.
We have shown similar trends in women treated for hyperthyroidism with propylthiouracil
and women treated with 5-acetylsalicylic acid for inflammatory bowel disease.
We have also shown that continuation of
breastfeeding is correlated with the cumulative amount of
reassuring counselling advice women receive from health
Duration of breastfeeding
In another recent study, we looked prospectively and closely at a group of nursing women who were reassured by Motherisk that the drugs they wanted to use were safe. We divided the women into two groups according to whether they eventually did or did not take our advice to continue the drugs and compared the duration of breastfeeding in the two groups. ( 5 )
We enrolled 88 women who were exclusively breastfeeding infants younger than 6 months. Follow-up interviews were conducted every 4 weeks until the women completely stopped breastfeeding or the infants reached 7 months of age.
Group 1 consisted of 69 women who reported that they continued the drugs after the counselling session; group 2 consisted of the remaining 19 who said they decided not to start therapy throughout the study period. The women in group 2 gave the following reasons for not continuing their medications: 18 (95%) "did not need" the drugs; and 1 (5%) was "told not to take the drug by a physician." Of the 18 women who did not need the medications, three still expressed concern about the toxicity of their medications for their breastfed infants. The two groups were not significantly different in demographic characteristics.
Of the 69 women in group 1, 36 (52%) introduced formula supplementation before infants reached 6 months of age; of 19 in group 2, four (21%) did so (P=.03). In group 1, 22 (32%) women completely stopped breastfeeding by the time their infants were 6 months of age (four women stopped breastfeeding by 3 months); only one (5%) of the 19 women in group 2 did so (P=.04).
Kaplan-Meier curve shows that the likelihood of women continuing exclusive breastfeeding decreases over time after the initial counselling session. Women who took drugs (group 1) tended to introduce formula earlier than those who did not (group 2) (P<.001). Hence, women in group 2 tended to breastfeed longer than those in group 1 (P<.03).
Overall, it appears that women who do not continue drug therapy breastfeed exclusively for longer and continue breastfeeding longer overall. A similar trend was observed in the analysis of disease-matched subgroups.
Our results indicate that maternal drug therapy during breastfeeding is a risk factor for relatively early introduction of formula supplementation and cessation of breastfeeding. Cumulative reassuring advice is associated with a better chance of continuation of breastfeeding; negative advice is associated with early termination of breastfeeding.3 Women who chose to continue drug therapy in the study5 (group 1) did not comply with breastfeeding as well as those who decided not to take drugs. Because we could not ethically have a control group who were not counselled positively about the safety of drugs, we cannot measure the effect of counselling.
What is the practical point for those who need to counsel nursing mothers taking chronic medication? You might succeed in reassuring them enough to initiate breastfeeding while receiving drug therapy, but eventually they will discontinue breastfeeding earlier than if they had not taken the drugs. Special efforts should be made to encourage these women not to stop breastfeeding through repeated reassuring counselling.
A: Recent studies reveal that women receiving chronic therapy tend to initiate breastfeeding much less often than mothers in the general population and, if they do initiate, discontinue it much earlier. While reassuring counselling is generally correlated with continuation of breastfeeding, women receiving chronic medications still discontinue breastfeeding earlier. Stressing the clear benefits of breastfeeding and the lack of apparent risk of drugs shown to be safe should be coupled with repeated reassurance to mothers during close follow up of their babies.
Shinya Ito, MD
Mary Lieu, MSC
Gideon Koren, MD, FRCPC
Taddio A, Ito S. Drugs in
breastfeeding. In: Koren G, editor. Maternal-fetal toxicology: a
clinician's guide. 2nd ed. New York, NY: Marcel Dekker; 1994.
Ito S, Moretti M, Chu M, Koren G.
Initiation and duration of breastfeeding in women receiving
antiepileptic drugs. Am J Obstet Gynecol 1995; 172:881-6.
Lee A, Ito S, Moretti M,
Callentes A, Chong D, Koren G. The safety of propylthiouracil
during breastfeeding; current medical practice [abstract]. Clin Invest
Med 1998;514(Suppl 21):S14.
Moretti M, Spiczynski Y, Hashemi
G, Koren G, Ito S. Prospective follow up of infants exposed
to 5-aminosalicylic acid containing drugs through maternal
milk [abstract]. Clin Invest Med 1998;514(Suppl 21):S16.
- Moretti M, Ito S, Koren G. Initiation and compliance with breastfeeding in women receiving medications. Pediatr Perinat Drug Ther. In press.
This issue of The Motherisk Newsletter is supported by SHOPPERS DRUG MART