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Motherisk Newsletters: Winter 1999, No. 11

Winter 1999, No. 11

Cancer Chemotherapy During Pregnancy?

Q: I have a patient who is 8 weeks pregnant. She has just been diagnosed with stage III Hodgkin's disease. The oncologist suggests that we delay chemotherapy until the second trimester. What are the effects of chemotherapy on the fetus after the first trimester? Where can I find reliable information on the subject?

The diagnosis of cancer during pregnancy is one of the most extreme scenarios in medicine where the creation of a new life may coincide with maternal death. This situation poses immense stress on the pregnant patient, her family and the medical staff. The occurrence of cancer in pregnancy is rare with an incidence of 0.07%-0.1% (1). It is conceivable that the current trend to defer pregnancy until later in life may increase the incidence of cancer in pregnancy. However, there is a paucity of information on the effect of pregnancy on cancer and the effects of the disease and its therapy on pregnancy outcome (2,3). Since significant advances have been made with current chemotherapeutic agents in increasing longevity and survival, it is a major challenge to ensure optimal treatment for the mother without causing harm to the fetus.

Most chemotherapeutic agents have been shown to inflict damage to rapidly dividing cells such as bone marrow, intestinal epithelium and the reproductive system. Animal studies suggest that the fetus would be sensitive to these agents, as fetal tissues have a high growth rate. This may result in spontaneous abortions or malformations (4).

Cancer chemotherapeutic drugs are potent teratogens. Currently, there is very little information on the effect of cancer chemotherapy on the fetus (5). The risk of malformations when chemotherapy is administered in the first trimester has been estimated to be approximately 10% for single agent chemotherapy regimens and 25% for combination chemotherapy (6,7). Thus chemotherapeutic agents should be avoided during the first trimester. There is no evidence of an increased risk of teratogenicity during second and third trimesters (5).

A recent report on a small series of breast cancer patients confirmed, in a prospective manner, that chemotherapy is indeed effective and safe when administered after the first trimester (8).

The long-term nonteratogenic effects of chemotherapy remain largely unknown. There have been reports on increased risk of stillbirth, low birth weight and intrauterine growth retardation following treatment in the second and third trimester (5,9). When chemotherapy is administered during pregnancy, delivery of the infant should be timed to avoid the chemotherapy nadir of adverse effects (e.g. blood cells) and its associated problems. Only a few reports associate chemotherapy administered to the mother with neonate hematopoietic depression which is self-limiting but increases the risk of neonatal infection and hemorrhage (10). Limited available information does not suggest that children, born to mothers who were treated with chemotherapy during pregnancy, may have impaired mental and physical development, or infertility (11). The incidence of second malignancies in these children should also be evaluated. To date there is only a single case report that describes the occurrence of multiple malignancies in a son of a patient with acute lymphocytic leukemia who was exposed in utero to cyclophosphamide and steroids. His twin sister was not affected (12). Antineoplastic agents administered systematically may reach clinically significant levels in breast milk, therefore breastfeeding is contraindicated (13,14).

The use of cytotoxic immunosuppressive drugs in nononcological disorders is increasing rapidly. These drugs are currently used in rheumatic disorder (especially in young women), post organ transplantation, etc. It should be emphasized that in non malignant conditions these medications are used at lower doses than in the treatment of tumors. Alkylating agents (mainly cyclophosphamide), and antimetabolites, 6 mercaptopurine and azathioprine are often used in these conditions (15).

A: Available data suggest that exposure to chemotherapy in the first trimester of pregnancy is associated with increased risk of major malformations. Exposure during the second and third trimesters does not result in major malformations, but may have non-teratogenic effects such as low birth weight. The brain develops throughout pregnancy, and may be affected later in pregnancy.

Since there is very little information on the various issues of cancer in pregnancy, including the effects of chemotherapeutic agents on the fetus, Motherisk has established the Consortium of Cancer in Pregnancy Evidence (CCoPE). An international group of oncologists, obstetricians, pediatricians, pharmacologists, geneticists and specialists in related fields, CCoPE develops evidence-based information on the diagnosis, management, prognosis and fetal outcome of cancer in pregnancy. Much of the information produced by CCoPE is now available on-line in Cancer in Pregnancy @
http://www.motherisk.org. Our hope is that CCoPE and this new website will become important resources for all those concerned with the optimal care and treatment of pregnant women with cancer, and their babies. Please be sure to visit this new website.

Michael Lishner, MD
Gideon Koren, MD, FRCPC, FAACT


  1. Sutcliffe SB. Treatment of neoplastic disease during pregnancy: maternal and fetal effects. Clin Invest Med 1985; 8: 333-338.
  2. Koren G, Weiner L, Lishner M, Zemlickis D, Finegan J. Cancer in pregnancy: identification of unanswered questions on maternal and fetal risk. Obstet Gynecol Surv 1990; 45: 509-514.
  3. Antonelli NM, Dotters DJ, Katz VL, Kuller JA. Cancer in pregnancy: A review of the literature. Obstet Gynecol Survey 1996; 51: 125-142.
  4. Sokal J, Lessmann EM. Effects of cancer chemotherapeutic agents on the human fetus. JAMA 1960; 172: 1765-1772.
  5. Zemlickis D, Lishner M, Koren G. Review of fetal effects of cancer chemotherapeutic agents. In: Koren G, Lishner M, Farine D (eds): Cancer in Pregnancy. Cambridge University Press, 1996; 168-180.
  6. Doll DC, Ringenberg S, Yarbro YW: Management of cancer during pregnancy. Arch Intern Med 148: 2058-2064, 1988.
  7. Nicholson Ho: Cytotoxic drugs in pregnancy: Review of reported cases. J Obstet Gynecol Br Common W. 1968; 75: 307-312.
  8. Berry DL, Theriault RL, Holmes FA, Parisi VM et al: Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17: 855-861.
  9. Zemlickis D, Lishner M, Degendrofer P, Panzarella T, Sutcliffe SB, Koren G: Fetal outcome following in utero exposure to cancer chemotherapy: The Toronto study. Arch, Intern Med 1992; 15: 573-576.
  10. Blatt J, Milvihill JJ, Ziegler JL et al: Pregnancy outcome following cancer chemotherapy. Am J Med 1980; 39: 828-832.
  11. Aviles A, Diaz-Maqueo JC, Talavera A, Guzman R, Garcia EL. Growth and development of children of mothers treated with chemotherapy during pregnancy. Current status of 43 children. Am J Hematol 1991; 136: 243-248.
  12. Zemlickis D, Lishner M, Erlich R, Koren G: Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratogenesis, Carcinogen, Mutagen 13: 139-143, 1993.
  13. Egan PC, Costanza ME, Dodion P, Egorin MJ, Bachur NR. Doxorubicin and cisplatin excretion into human milk. Can Treat Rep 1985; 69: 1387-1389.
  14. De Vries EGE, Van Der Zee AGJ, Uges DRA, Sleijfer DTH. Excretion of platinum into breast milk. Lancet 1989; 1: 497.
  15. Ebert U, Loffler H, Kirch W. Cytotoxic therapy and pregnancy. Pharmacol Ther 1997; 74: 207-220.


Q: One of my patients, who is now 8 weeks pregnant, just read in the newspaper that dextromethorphan (DM), an antitussive found in a variety of cough medicines, caused birth defects in chicken embryos. The author of the study stated that even one dose could be dangerous and that he would never allow his wife to use this drug if she were pregnant. My patient is understandably very concerned because last week she was suffering from a nasty cough and had been advised by her pharmacist to use a cough mixture containing DM, which she subsequently took for several days. How should I advise her?

Animal studies can, but do not always, predict whether a drug will be teratogenic in humans. The main role of animal studies is to help researchers understand the mechanisms of teratogenicity. Unfortunately, animal studies were poor predictors in the case of thalidomide; the drug was tested on rats and mice, but did not originally produce birth defects. (1) On the other hand, some drugs have been found teratogenic in animals and not in humans. (2,3)

Today, when new drugs are screened for teratogenicity, three different animal models are required for testing. Quite frequently, when certain drugs are tested on different animal species, birth defects occur, as happened in the DM study. (4) Interspecies differences regarding the teratogenicity of drugs can result from differing pharmacokinetic processes that determine the crucial concentration-time relationships in an embryo.

Protein binding in the mother is also an important determinant of placental transfer because only free concentrates in maternal plasma can reach equilibration with the embryo during organogenesis. This parameter differs greatly across species (eg, valproic acid, which has five times higher free concentrations in mice and hamsters than in monkeys and humans). Laboratory animals usually eliminate drugs much faster than humans; the drastic drug fluctuations that occur during teratogenicity studies of animals, therefore, do not happen to the same degree in humans. (5) Animals are also given far higher doses of drugs than humans would ever receive (eg, as in the clarithromycin study (3)).

Extrapolating data from these studies to humans and subsequently publishing supposed effects in the mass media, without a clear understanding of the differences, can cause women and their health professionals unnecessary anxiety. This kind of information sells newspapers but does nothing to inform the public of the real risks or safety of drugs during pregnancy.

Over the years, many studies in the literature have selectively reported research results, which ultimately find their way into the mass media. (6,7) Papers also document the bias against publication of reassuring studies. (8-10) The public should be wary of gaining medical knowledge through newspaper and other media reports.

The only way to ascertain the ultimate risk or safety of drugs during pregnancy is to do human studies. Prospective, controlled, epidemiologic studies of the pregnancy outcomes of women who consumed a particular drug during pregnancy is one example. Even this type of research is not ideal because, for obvious ethical reasons, women cannot be enrolled in randomized, controlled studies, and because the limited size of the studies means they do not have the statistical power to detect increased risk of rare malformations. Another example is case-control studies, where drug use among mothers whose babies have a specific malformation is compared with that of mothers whose babies do not. This method has a much higher sensitivity, but is more prone to bias.

Due to the unjustified level of anxiety stirred up by inappropriate reporting of the chick-embryo study, we decided to carry out a prospective controlled study at The Motherisk Program to provide additional evidence-based information on human exposures. This information will be added to that of two previous studies on the safety of using DM during pregnancy. The Collaborative Perinatal Project monitored 50 282 mother-child pairs, 300 of whom took DM in the first trimester and had no increase in birth defects above the 1% to 3% baseline rate. (11) A surveillance study of 59 women who had used DM in the first trimester documented one malformation. (12) Upon completion, this study will provide further evidence to guide women and their health professionals in making informed decisions about use of DM during pregnancy. (13)

A: You may reassure your patient that she did not put her baby at risk by using this substance. Dextromethorphan has been on the market for many years and has never been implicated as a human teratogen. Furthermore, chick embryos are not a good model for predicting teratogenic potential in humans and, consequently, were abandoned as such more than 30 years ago.

Adrienne Einarson, RN
Gideon Koren, MD, FRCPC

  1. Newman CGH. Clinical aspects of thalidomide embryopathy--a continuing preoccupation. Teratology 1985;32:133-44.
  2. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338(16):1128-37.
  3. Einarson A, Phillips E, Mawji F, D'Alimonte D, Schick B, Addis A. A prospective multicentre study of clarithromycin in pregnancy. Am J Perinatol 1998;15(9):523-5.
  4. Andalaro V, Monaghan D, Rosenquist T. Dextromethorphan and other N-methyl-d-aspartate receptor antagonists are teratogenic in the avian embryo model. Pediatr Res 1998;43:1-7.
  5. Nau H. Species differences in pharmacokinetics and drug teratogenesis. Environ Health Perspect 1986;70:113-29.
  6. Cleophas RC, Cleophas TJ. Is selective reporting of clinical research unethical as well as unscientific? Int J Clin Pharmacol Ther 1999;37(1):1-7.
  7. Newcombe RG. Towards a reduction in publication bias. BMJ (Clin Res Ed) 1987;295(6599):656-9.
  8. Proudfoot AD, Proudfoot J. Medical reporting in the lay press. Med J Aust 1981;10(1):8-9.
  9. Koren G, Klein N. Bias against negative studies in newspaper reports of medical research. JAMA 1991;266(13):1824-6.
  10. Kleijnen, Knipschild P. Review articles and publication bias. Arzneimittelforschung 1992;42(5):587-91.
  11. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton, Md: Publishing Sciences Group; 1997.
  12. Aselton P, Jick H, Milunsky A, Hunter J, Stergachis A. First trimester drug use and congenital disorders. Obstet Gynecol 1985;65:451-5.
  13. Einarson A, Lyszkiewicz D, Koren G. The safety of dextromethorphan in pregnancy: a prospective controlled study, Colorado 1999 [abstract]. Teratology 1999;59(6):377.


The Motherisk HIV Healthline and Network will be two years old on December 1, World AIDS Day. This joint program of the Motherisk and HIV programs at The Hospital for Sick Children provides information and counseling on HIV in pregnancy to women and their healthcare providers. It also maintains a national HIV pregnancy registry to monitor the long-term health of children exposed to antiretroviral therapies during pregnancy and as infants. Antiretroviral drugs are used to reduce the risk of mother-to-child transmission and maintain the mother's health.
The Healthline consistently receives calls from pregnant women with HIV infection wanting to enroll children in the registry. Exposed children are examined annually following the six-month check-up when the child's HIV status can usually be confirmed. The registry, started in Ontario, is now expanding nationally.

[Year 2 increase in number of calls: 30%]
General requests for information
Calls from healthcare providers
Calls from community health or AIDS agencies
Calls from women with HIV infection
Questions re. occupational or sexual exposure incidents
Registry information
Calls from pharmacists or drug companies

For more information please call 1-888-246-5840.


Q: Is there any way to predict whether a drug taken by a mother is safe for a suckling baby, or is it just trial and error? One of my patients is receiving lithium for manic depression. She wishes to breastfeed, but clinically there is no way she can discontinue the drug. My sources say the drug is incompatible with breastfeeding.

Carole Boyer (far left) and Eric Gervais (far right) of Duchesnay Inc. and Lynn Krepart (centre) of the Canadian Foundation for Women's Health present the first Duchesnay Award to Dr. Shinya Ito (right) of HSC's Motherisk Program, for his research entitled, Maternal use of beta-blockers during breastfeeding.

Many women need drug therapy during the postpartum period to treat chronic or acute medical conditions. Mothers are naturally concerned about the potential risk to their suckling infants from drugs introduced through milk. Hence, it is crucial to identify methods that accurately define the safety or risk of such exposures, because every year scores of new drugs are introduced to the market.

For many years, the ratio between drug concentrations in maternal milk (m) and plasma (p) was used to estimate how much was getting through to a baby. The higher the m/p ratio, the higher concentrations were available to a baby, people assumed. This approach, however, was too simplistic from a pharmacokinetic viewpoint, because a drug's clearance rate from a baby's body is as important as the amount of drug offered to the baby.

Several years ago the Motherisk team developed a new concept, the Exposure Index (EI), which incorporated both the m/p ratio and the clearance rate of the drug (1). The formula is:

EI = 100 x m/p ratio
clearance (mL/kg/min)

The EI, in simple terms, is the percentage of maternal dose per kg available to the baby. This equation implies that, even if a drug appears at higher concentrations in milk than in maternal plasma, the clearance rate of the drug will define its safety. Experimental data show that this new concept better estimates the risk to the baby than the old m/p ratio (1).

In the case of lithium, which has a high m/p ratio, the EI is unsafely high in many infants, but, due to individual (faster) renal clearance rates, is quite low in many others. In several recent cases, we allowed women receiving lithium, who attended Motherisk, to breastfeed provided lithium levels were measured in breastmilk or neonatal blood. In other cases, such measurements proved the drug unsafe. We concluded that therapeutic drug monitoring could help ascertain whether breastfeeding was safe for women receiving drugs for which there are readily available methods of measurements.

Another relatively common misconception among physicians is in their approach to breastfeeding for women who drink alcohol or smoke cigarettes. While common sense dictates not drinking while breastfeeding, many women are chemically dependent and are unable to discontinue drinking. Advising them not to breastfeed ignores the increased morbidity and mortality among formula-fed babies. DR Jack Newman eloquently stated the case: "Those using drugs are also at the risk on many levels for increased infant morbidity and mortality. It is when the socioeconomic situation is the worst that breastfeeding has the greatest benefit." (2)

A: The amount of drug available to a baby through breastmilk is estimated as the percentage of maternal dose per kg ingested by the baby. Because infants' clearance rate of many drugs is slower than adults', however, the true level of the drug circulating in the infant's blood might be much higher. Because lithium can be measured in plasma, it is prudent to measure it in milk and to estimate the "baby dose." If a baby shows any adverse effects, lithium levels should be measured in its blood.

Gideon Koren, MD, FRCPC
Myla Moretti, MSC
Shinya Ito, MD


  1. Ito S, Koren G. A novel index for expressing exposure of infants to drugs in breastmilk. Br J Clin Pharmacol 1994;38:99-102.
  2. Newman J. Drugs in breastfeeding. Motherisk Newsletter 1995;4:4.


Q: I am counseling patients to take folic acid when they plan pregnancy and during early pregnancy. Is there any proof that counseling really causes women to comply?

Folic acid and neural tube defects
Accumulation of data from the last 14 years, in the form of randomized controlled trials, (1,2) non-randomized intervention studies, (3,4) and observational studies, 5-8 has provided evidence that periconception ingestion of folic acid can reduce the number of pregnancies affected by neural tube defects (NTDs), especially among high-risk patients and low-risk primigravidas. (9) Available evidence suggests the possibility of averting at least 50% (10) and perhaps 72% (3) of cases of NTDs if women at high risk of having babies with NTDs consume 4.0mg/d of folic acid during the critical stage of neural tube development in subsequent pregnancies. Similarly, it might be possible to decrease the incidence of NTDs in low-risk pregnancies by 40% to 60% if women consume 0.4mg/d of folic acid during the critical stage of neural tube closure. (10,11)

Reflecting these levels of evidence, current guidelines recommend that low-risk women of reproductive age who are planning pregnancy should supplement their diets with 0.4mg/d of folic acid and high-risk women of reproductive age who are planning pregnancy should supplement their diets with 4.0mg/d. (12-14)

Two important issues in translating this breakthrough knowledge into a primary prevention strategy is that, on average, Canadian and American women consume only half the needed 0.4mg/d of folic acid, (15) and that at least 50% of pregnancies are unplanned. (16) Therefore, informing women before conception about their preventable risk for having babies with NTDs is crucial.

Effectiveness of counseling
A recent study conducted by the Motherisk Team assessed the effectiveness of our folic acid supplementation counseling program by comparing folic acid intake in a group of counseled women with that in a group of uncounseled women. (15) This prospective study chose subjects from among patients planning pregnancy who called Motherisk during the 15 weeks between May 2 and August 19, 1994. To be included in the study, patients had to have no prior knowledge of the need to supplement with folic acid and to have had counseling on folic acid supplementation from the Motherisk Program. Then, from November 1994 to April 1995, we contacted these women to ascertain their compliance with our advice.

For a control group, we collected women who were <14 weeks' gestation at the time of their first call to Motherisk, who had not been counseled to take folic acid, and who, before pregnancy, had not been aware of the importance of folic acid. We corrected for the possibility that women might have received information on folic acid supplementation from sources other than the Motherisk Program before their call.

Comparisons between counseled and uncounseled groups were made using Student's t test for unpaired data or the x2 test, where appropriate.

In the 15-week study period, we followed up with 145 women. Their characteristics are shown in Table1. Most were between 30 and 34 years old, nulliparous, and in the middle of the socioeconomic scale.

At follow up, 66 of the 145 women (46%) had conceived. Whether or not they had conceived, 105 women (72%) were taking folic acid at the time of the follow-up call. Of these, 103 who were rated low risk by the counselor at the initial call were taking 0.4 to 1.0mg/d of folic acid, and two women were taking 5.0mg/d. Those who did not take folic acid cited various reasons for their decision not to supplement (Table2).

Women who took folic acid (72%) were different from women who did not (28%) in that they were more likely to abstain from cigarettes, alcohol, and cocaine and were more likely to have received many reminders about the importance of folic acid (Table1).

At the time of the follow-up call, 55 (83%) of the 66 women who had conceived were still gravid, six had miscarried, one had a tubal pregnancy, and four had delivered healthy infants without congenital defects. Of the 66 pregnant women, 60 (91%) had complied with Motherisk's advice and taken folic acid: 47 (71%) took folic acid before, during, and after the critical period for neural tube development; and 13 (20%) started folic acid supplementation once pregnancy was diagnosed. At follow up, 79 women (54%) had not conceived: 45 were taking folic acid (42 were still planning pregnancy), and 34 were not taking folic acid (14 were still planning pregnancy).

In our control group of 147 women who were <14 weeks' gestation at initial contact, only 25 (17%) began taking folic acid before conception, significantly fewer than among the counseled women (47 of the 66 who conceived [71%], P=.0001).

Table 1. Characteristics of women planning pregnancy
Mother's age at initial telephone call (y) 32.0 + 4.2 (range 23-43) 32.5 + 4.9 (range 23-48) .52
Gravidity at initial call


40 (38%)
31 (30%)
17 (16%)
8 (8%)
8 (8%)

12 (30%)
17 (42%)
7 (18%)
4 (10%)

Parity at initial call


21 (52%)
14 (35%)
3 (8%)
2 (5%)

55 (52%)
28 (27%)
17 (16%)
05 (5%)

Socioeconomic score*

(Mean 51.9)

37 (35%)
13 (12%)
33 (31%)
21 (20%)
1 (1%)
(Mean 50.2)

15 (38%)
6 (15%)
12 (30%)
7 (18%)

Time between initial call and follow up (wk) 30.5 + 9.6
range from 12-45
28.7 + 8.7
range 14-45
Product used

Jamieson (1 mg)
Materna (1 mg)
Orifer-F (0.8 mg)
Centrum Forte (0.4 mg)
Other (0.4 - 0.99 mg)
Other (>1 mg)

36 (34%)
37 (35%)
2 (2%)
4 (4%)
15 (14%)
11 (10%)

Pregnant at follow up?


60 (57%)
45 (43%)

6 (15%)
34 (85%)

Smoking at follow up


98 (93%)
7 (7%)

31 (78%)
9 (22%)

Alcohol use at follow up

<5 drinks/wk
>5 drinks/wk

97 (92%)
8 (8%)

27 (68%)
10 (25%)
3 (8%)

Cocaine use at follow up

At least once since initial call

105 (100%)

38 (95%)
2 (5%)

Use of folate-depleting drug(s)
at follow up



* Index used does not provide scores for people in certain occupations. In the uncounseled population, three were students, four were unemployed, four were self-employed, and 41 described themselves as homemakers.
One patient reported starting carbamazepine therapy for tonic-clonic generalized epilepsy and supplementing with 5mg/d of folic acid.

Table 2. Patients' reasons for not taking folic acid:
As stated at follow up.
N = 40
No longer planning pregnancy; no further reasons given
Husband laid off, recent divorce, planning in vitro fertilization in future
3 (1 each)
Concurrent illness and drug therapy were too much to think about
Folic acid made her sick
Her physician did not believe in the benefits of folic acid
Did not know it had to be taken before pregnancy
Had heard nothing about folic acid
No reasons given
Did not think the "fuss" was "for real"
Did not have enough information to convince her
Found out she was 6 weks pregnant a week after initial call

Our study indicates that counseling women before pregnancy substantially improves their compliance with folic acid supplementation. In a recent study, we showed that only a small proportion of family physicians in Toronto routinely and correctly advise women on folate supplementation.16 These results taken together suggest that, if physicians or other health professionals counsel women to take folic acid supplementation, many fetuses will avoid exposure to low levels of folic acid.

It is conceivable that the women in our study were inherently more motivated to comply with folic acid supplementation, given that they were a self-selected population who voluntarily sought advice from Motherisk. Yet, without our counseling, only 17% of our callers would have effectively protected their fetuses with sufficient folic acid. Regardless of this selection bias, our study indicates that counseling can affect patient behaviour.

A: Counseling can successfully influence women's compliance with folic acid supplementation. We expect many women will have never heard or read about the beneficial effects of periconception folic acid supplementation. Effective counseling by health professionals can play a pivotal role in reducing infants' risk of neural tube defects.

Anne Pastuszak, MSc
Dimple Bhatia , BSc
Bunmi Okotore, MD
Gideon Koren, MD, FRCPC, FACCT

  1. Laurence KM, James N, Miller M, Tennant GB, Campbell H. Double-blind randomized controlled trial of folate treatment before conception to percent recurrence of neural-tube defects. BMJ 1981; 282:1509-11.
  2. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-7.
  3. Smithells RW, Nevin NC, Seller MJ, et al. Further experience of vitamin supplementation for the prevention of neural tube defect recurrences. Lancet 1983;1:1027-31.
  4. Vergel RG, Sanchez LR, Heredero BL, et al. Primary prevention of neural tube defects with folic acid supplementation: Cuban experience. Prenat Diagn 1990; 10:149-52.
  5. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260:3141-5.
  6. Bower C, Stanley FJ. Dietary folate as a risk factor for neural-tube defects: evidence from a case-control study in Western Australia. Med J Aust 1989; 150:613-9.
  7. Mills JL, Rhoads GG, Simpson JL, Cunningham GC, Conley MR, Lassman MB, et al. The absence of a relation between the periconceptional use of vitamins and neural tube defects. N Engl J Med 1989;321:430-5.
  8. Milunsky A, Jick A, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 262:2847-52.
  9. Czeizel A, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5.
  10. Centers for Disease Control. Recommendations for use of folic acid to reduce the number of spina bifida cases and other neural tube defects. JAMA 1993;269:1233-8.
  11. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrence of neural tube defects. JAMA 1993;269:1257-61.
  12. SOGC Genetics Committee. Recommendations on the use of folic acid for the prevention of neural tube defects. J SOGC 1993;56(Suppl):41-6.
  13. Van Allen M, Fraser FC, Dallaire L, Allanson Y, McLeod DR, Andermann C, et al. Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects. Can Med Assoc J 1993;149:1239-43.
  14. Canadian Task Force on the Periodic Health Examination. The periodic health examination: 1994 update. 3. Primary and secondary prevention of neural tube defects. Can Med Assoc J 1994;151:159-66.
  15. Pastuszak A, Bhatia D, Okotore B, Koren G. The effectiveness of pre-conceptional counseling on women's compliance with folic acid. In: Maternal-fetal toxicity. 3rd ed. New York, NY: Marcel Dekker; 1999.
  16. Koren G. Periconception folic acid supplementation; knowledge and practice of Canadian family physicians. Can Fam Physician 1997;43:851-2.

Maternal-Fetal Toxicology: A Clinician's Guide. Third Edition. Published by Marcel Dekker, NY. Updated and expanded. Includes new information on the risks of natural products in pregnancy, drugs and breastfeeding, and other important findings of the Motherisk Team.

This issue of The Motherisk Newsletter is supported by SHOPPERS DRUG MART
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