Doxylamine

Name: DOXYLAMINE
Class: Antihistamine/Antiemetic
Risk Factor: A

Fetal Risk Summary

Doxylamine, an antihistamine of the ethanolamine class, is approved for use as a sedative, either alone or in combination with other agents in cough and cold preparations. It is not used in the United States for the symptomatic relief of hypersensitivity reactions, most likely because of its pronounced sedative effects.
The antihistamine was a component of the proprietary product, Bendectin, which contained equal concentrations of doxylamine, pyridoxine (vitamin B6), and dicyclomine (an antispasmodic). Bendectin was marketed in 1956 for the prevention and treatment of nausea and vomiting during pregnancy. The product was reformulated in 1976 to eliminate dicyclomine because that component was not found to contribute to the antiemetic effectiveness. A similar Canadian two-drug formulation (doxylamine and pyridoxine), Diclectin, was marketed in 1978. More than 30 million women have taken this product during pregnancy, making it one of the most heavily prescribed drugs for this condition. The United States manufacturer ceased producing the drug combination in 1983 because of litigation and adverse media coverage over its alleged association with congenital limb defects. The fixed two-drug combination, although no longer available in the United States, continues to be produced in Canada and the individual components are marketed worldwide by various manufacturers.
Six studies in rodents and nonhuman primates have not observed teratogenic effects with Bendectin or its components (1,2,3,4,5 and 6), but dose-related toxicity was observed in three studies. In a 1968 publication, the reproductive effects of dicyclomine, doxylamine, and Bendectin (the three-drug combination of doxylamine [10 mg], dicyclomine [10 mg], and pyridoxine [10 mg]) in rats and rabbits were reported (1). Dicyclomine and doxylamine were given as pure compounds, whereas Bendectin was administered as pulverized tablets. In rats, dicyclomine and doxylamine (10–100 mg/kg/day) (15–150 times the maximum recommended human dose [four tablets] for a 60-kg human [MRHD]) were given orally for 80 days or more before pregnancy and continued during one (dicyclomine) or two (doxylamine) successive liters. The Bendectin group received 3–60 mg/kg/day (5–90 times the MRHD) orally beginning on the first day of gestation and continued throughout the remainder of the study. First-generation male and female offspring from the control and 60 mg/kg/day groups were then bred (nonsibling matings) and their progeny examined. Compared with nonexposed controls, no increase in congenital malformations or other adverse effects were noted in the pregnancy outcomes of the three drug groups. The one exception appeared to be a small dose-related decrease in fetal weight that was observed in the dicyclomine and doxylamine groups. Pregnant rabbits were administered 10–100 mg/kg/day (15–150 times the MRHD) orally of dicyclomine or doxylamine, or 3–30 mg/kg/day (5–45 times the MRHD) orally of Bendectin on days 9 through 16 of gestation (1). Similar to the study with rats, no adverse effects in pregnancy outcomes were noted when compared with controls except when toxic (100 mg/kg/day) doses were used in the pure drug groups (1).
A 1993 Reference studied the effects of three antiemetic histamine H1 antagonists, doxylamine, chlorcyclizine, and promethazine, on the skeletons of rat fetuses exposed during organogenesis (days 7–13) (2). Doxylamine was given orally at doses of 500 and 750 mg/kg (750 and 1,125 times the MRHD). Compared with controls, a dose-dependent loss of skeletal integrity and marked fragility occurred with each antihistamine (2). The investigators concluded that the fragility was due to a defect in joint development rather than to intrauterine growth retardation.
No increase in malformations was observed in rats given Bendectin (two-drug combination) during organogenesis in doses of 0, 200, 500, and 800 mg/kg/day (3). Both maternal and fetal toxicity were evident at the two highest doses. Developmental toxicity observed was reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day).
Three of the reproduction studies involved nonhuman primates (4,5 and 6). In an unpublished study, rhesus monkeys were given a dose of 7 mg/kg/day (10 times the MRHD) without producing malformations (4). A second study, published in 1985, administered pulverized Bendectin (10 mg doxylamine plus 10 mg pyridoxine) to pregnant cynomolgus monkeys, rhesus monkeys, and baboons (5). A commercial preparation of doxylamine (Decapryn) was used in some baboons to reduce the total amount of drug if they would not take Bendectin. Nonexposed controls were used in each species. Most animals received the study drugs daily from gestation day 22 to 50, the major period of organogenesis (5). Cynomolgus and rhesus monkeys were given doses 10–40 times the MRHD, whereas baboons received doses 1–10 times the MRHD of Bendectin or 10 times the MRHD of doxylamine. A few cynomolgus monkeys (short-term exposure group) received Bendectin doses 20 times the MRHD for 4 consecutive days on gestation days 22–25, 26–29, 30–33, 34–37, or 38–41. Some of the long-term exposure monkey groups, all of the short-term exposure groups, and all of the baboon fetuses were removed by hysterotomy prenatally at day 100 of gestation. The remaining monkey fetuses were delivered at term (150–160 days). In the offspring examined prenatally, the incidence of ventricular septal defect (VSD) was 40% (6 of 15) in cynomolgus monkeys, 0% (0 of 8) in cynomolgus monkey short-term exposure groups, 18% (2 of 11) in rhesus monkeys, 23% (3 of 13) in Bendectin-exposed baboons, and 20% (1 of 5) in doxylamine-exposed baboons. The VSD was restricted to the muscular portion of the septum in 91% (11 of 12). No other defects were observed in the monkeys and no dose response was evident among the long-term treated groups. In addition to the VSD, one baboon fetus (drug group not specified) had exophthalmia, micrognathia, reduction of first and fifth digits on both hands, facial hemangioma, and ambiguous genitalia, and was small for gestational age. The cause of the multiple defects was unknown, but a genetic basis for the anomalies could not be excluded. (Karyotyping was not available at that time.) (5). At term, no cases of VSD were found in nine cynomolgus and four rhesus monkey offspring, but one cynomolgus monkey had a mitral valve defect. Data from the author's laboratory indicated a very low incidence of spontaneous VSD in the three species: 0.3% (1 of 297) cynomolgus monkeys; 0% (0 of 1,692) rhesus monkeys; 1.6% (1 of 61) baboons (5). The authors concluded, therefore, that the results suggested a delay in closure of the ventricular septum but that closure would occur before birth (5).
In the second part of the above investigation, daily Bendectin (doxylamine plus pyridoxine) doses 2, 5, and 20 times the MRHD were administered double-blind to cynomolgus monkeys (N=69) from gestational days 22 through 50 (6). A control group (N=21) received placebo tablets containing inert excipients and coatings similar to those in Bendectin. The doses for the four groups (three active, one placebo) were prepared by the manufacturer, and their identity was unknown to the researchers. Delivery occurred at term (approximately 155 days of gestation). No congenital malformations were noted, and no evidence of embryo, fetal, or maternal toxicity was observed.
More than 160 cases of congenital defects have been reported in the literature or to the FDA as either “Bendectin-induced” or associated with use of the drug in the 1st trimester (7,8,9,10,11 and 12). Defects observed included skeletal, limb, and cardiac anomalies as well as cleft lip or palate. A 1983 study found an association between Debendox (three-drug formulation) and clefts of the lip, palate, or both, although the authors stated that the association may have been due to chance alone (13).
In a 1989 study, the association between maternal use of marijuana and childhood acute nonlymphoblastic leukemia (ANLL) was investigated (see Marijuana) (14). An incidental finding was that the relative risk (RR) for ANLL in offspring of case mothers who used antinauseant medication was 1.75 (95% confidence interval [CI] 0.98–3.20) (p=0.06). A statistically significant dose-response relationship was observed when the RR increased to 2.81 if the use of antinauseant medication continued for more than 10 weeks. Although not all of the mothers used Bendectin, most of them specifically named the product (14). However, several factors make a causal relationship between Bendectin and ANLL unlikely, including the possibility of recall bias between cases and controls, the absence of biological plausibility, the likelier possibility that the leukemia was induced by other toxins (e.g., marijuana, herbicides, or pesticides), and the lack of other reports of such an association.
A possible association between doxylamine-pyridoxine and diaphragmatic hernia was reported in 1983 and was assumed to reflect earlier findings of a large prospective study (12). Authors of the latter study, however, cautioned that their results could not be interpreted, even when apparently strong associations existed, without independent confirmation (15,16). In a large case-control study, infants exposed to the combination in utero had a slightly greater RR of 1.40 for congenital defects (17). The risk was more than doubled (RR 2.91) if the mother also smoked. An increased risk for heart valve anomalies (RR 2.99) was also found. A minimal relationship was found between congenital heart disease and doxylamine (Bendectin) use in early pregnancy in another 1985 report comparing 298 cases with 738 controls (18). The authors went to great efforts to establish that their drug histories were accurate. Their findings provided evidence that if an association existed, it was very small.
In one of the above studies, an association was discovered between Bendectin and pyloric stenosis (RR 4.33 to 5.24), representing about a 4-fold increase in risk for this anomaly (17). Similarly, the Boston Collaborative Drug Surveillance Programs reported preliminary findings to the FDA indicating a 2.7-fold increase in risk (19). A 1983 case-control study, however, found no association between Bendectin use and the anomaly (20). In evaluating these three reports, the FDA considered them the best available information on the topic, but concluded that no definite causal relationship had been shown between Bendectin and pyloric stenosis (19). In addition, the FDA commented that even if there were evidence for an association between the drug and the defect, it did not necessarily constitute evidence of a causal relationship since the nausea and vomiting themselves, or the underlying disease causing the condition, could be responsible for the increased risk (19). A 1984 study, which was not included in the above FDA evaluation, found a possible association with pyloric stenosis but could not eliminate the possibility that it was due to other factors (21). Compared with a control group, the odds ratio (OR) for pyloric stenosis in the offspring of mothers using Bendectin was 2.5 (95% CI 1.2–5.2). However, the authors stated that a conclusion supporting a causal association was not warranted because of the absence of a plausible biologic basis for the defect and conflicting results from other studies (21). Of interest, the Birth Defects Encyclopedia describes the etiology of pyloric stenosis (i.e., congenital hypertrophic pyloric stenosis) as probably polygenic and sex-modified, with an occurrence rate of 1:250 births (1:200 males; 1:1,000 females) (22).
The evidence indicating that doxylamine-pyridoxine is safe in pregnancy is impressive. A number of large studies, many reviewed in a 1983 article (23), have discovered no relationship between the drug combination and birth weight or length, head circumference, gestational age, congenital malformations, or other adverse fetal outcomes (24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39 and 40). An editorial accompanying the review article pointed out that Bendectin met none of the criteria for judging that a drug was a teratogen (41). One study was unable to observe chromosomal abnormalities associated with the drug combination, whereas a second study found that use of the drugs was not related to the Poland anomaly (unilateral absence of the pectoralis major muscle with or without ipsilateral hand defect) (42,43).
The Northern California Kaiser Permanente Birth Defects Study, published in 1989, prospectively studied the occurrence of 58 categories of major congenital defects in 31,564 newborns in relation to maternal Bendectin use (44). The OR for any major anomaly and Bendectin was 1.0 (95% CI 0.8–1.4). Three categories of defects were statistically associated with the drug: microcephaly (OR 5.3, 95% CI 1.8–15.6); congenital cataract (OR 5.3, 95% CI 1.2–24.3); and lung malformations (OR 4.6, 95% CI 1.9–10.9). However, this was the exact number of associations that would have been expected by chance alone (44). The authors then reviewed an earlier independent study that did not involve Bendectin and found strong positive associations of microcephaly and congenital cataract with vomiting in pregnancy (44). They concluded, therefore, that Bendectin use during the 1st trimester was not associated with an increase in congenital malformations and that the associations found were unlikely to be causal (44).
A meta-analysis of 17 studies involving the use of Bendectin in pregnancy was published in 1988 (45). The OR 1.01 (95% CI 0.66–1.55) for all studies indicated that Bendectin was not related to congenital defects. The studies were then separated by study type (cohort and case-control studies), and again, no relationship to birth defect outcomes was found (45). Another meta-analysis, published in 1994, examined 16 cohort and 11 case-control studies that had reported birth defects in pregnancies exposed to Bendectin during the 1st trimester (46). The RR of any birth defect in association with exposure to Bendectin was 0.95 (95% CI 0.88–1.04). The RR and 95% CI intervals for specific defects were: cardiac (0.90, 0.77–1.05), central nervous system (1.00, 0.83–1.20), neural tube (0.99, 0.76–1.29), limb reduction (1.12, 0.83–1.48), genital tract (0.98, 0.79–1.22), oral clefts (0.81, 0.64–1.03), and pyloric stenosis (1.04, 0.85–1.29). These results indicate that the use of Bendectin during the 1st trimester is unlikely to be associated with congenital malformations (46).
A five-part analysis of the medical literature involving Bendectin and pregnancy outcomes, published in 1995, was used as a demonstration of methodology to determine if a drug presented a human reproductive hazard (47). Some of the legal history surrounding Bendectin's alleged reproductive hazards was also reviewed. The analysis included: (a) analysis of human epidemiologic studies, (b) the relationship between the secular trend of birth defects and the population exposure to drugs, (c) the ability to develop an animal model, (d) analysis of dose-response relationships and pharmacokinetics of the drug in animals and humans, and (e) the biological plausibility for the alleged teratogenicity (47). The author reviewed eight in vitro studies that examined the toxicity, mutagenicity, teratogenicity, and other toxicities of doxylamine. None of these studies found toxicity at serum concentrations obtainable in humans. Moreover, the author emphasized the fact that in vitro studies, by themselves, cannot establish human teratogenicity (47). Based on the total data presented in this analysis, a strong case was made for the contention that Bendectin has no measurable teratogenic effects. In response to this and other publications, however, an intense debate in the scientific literature has developed between some who contend that Bendectin is safe and a proponent of the view that Bendectin induces limb reduction defects (48,49,50,51,52 and 53).
Interestingly, a population-based case-control study conducted in 1982–1983 by the Atlanta Birth Defects Case-Control Study and published in 1999 found a protective effect from Bendectin for congenital heart defects (54). The use of antiemetic medication, particularly Bendectin (two- and three-drug combinations), in early moderate to severe nausea during pregnancy was associated with a lower risk for heart defects compared with the absence of nausea (OR 0.67, 95% CI 0.50–0.92), and nausea without medication use (OR 0.70, 95% CI 0.50–0.94). The authors concluded that the results suggested that pregnancy hormones, other factors, or a component of Bendectin (most likely pyridoxine) may be important for normal heart development (54).
In spite of the abundant evidence supporting the safety of doxylamine-pyridoxine in pregnancy, the adverse media publicity and litigation proceedings surrounding Bendectin have affected the use of the combination in other countries. A 1995 article briefly reviewed the history of Bendectin in the United States and compared it with a similar Canadian product, Diclectin (55). Diclectin is the drug of choice for the treatment of emesis in pregnancy as specified by a Canadian Department of Health and Welfare task force, and is labeled for this indication. It is used less frequently, however, than another antihistamine, dimenhydrinate (Gravol; Dramamine in the United States), that is not specifically labeled for pregnancy use. The reason for this appears to be a fear of possible teratogenicity and subsequent litigation (55).
In summary, the preponderance of in vivo data supports the assessment that the fixed combination of doxylamine-pyridoxine is safe in human pregnancy, including the 1st trimester. Positive associations with congenital malformations have been observed but probably reflect outcomes that have occurred by chance or are the consequences of nausea and vomiting itself. Moreover, these reports do not consistently describe a specific syndrome or group of malformations. Therefore, pregnant women who request medication for nausea and vomiting can be offered this drug combination, but, as with any treatment during pregnancy, the available evidence should be reviewed with them to obtain their informed consent before initiating therapy.

Breast Feeding Summary

No reports describing the use of doxylamine or the fixed combination of doxylamine-pyridoxine during human lactation have been located. Because the combination is used only for the prevention or treatment of nausea and vomiting during pregnancy, it is doubtful if such reports will occur.
Both components of the fixed combination, however, are available as single agents. Pyridoxine is excreted into breast milk but, in the doses present in the antiemetic combination, presents no risk to a nursing infant (see also Pyridoxine). Doxylamine is an antihistamine that is used not only as an antiemetic, but also as a hypnotic and in cough and common cold preparations. The molecular weight of doxylamine succinate, about 389, is low enough that passage into breast milk should be expected. The effects on a nursing infant, if any, are unknown, but sedative and other antihistamine actions are a potential concern. The manufacturer of at least one doxylamine preparation states that the drug is contraindicated during nursing (56).

References

1. Gibson JP, Staples RE, Larson EJ, Kuhn WL, Holtkamp DE, Newberne JW. Teratology and reproduction studies with an antinauseant. Toxicol Appl Pharmacol 1968;13:439–47.
2. Sturman G, Freeman P, Bailey AR, Meade HM, Seeley NA. Loss of skeletal integrity in rat fetuses from dams treated with histamine H1 antagonists. Agents Actions 1993;38:C185–7.
3. Tyl RW, Price CJ, Marr MC, Kimmel CA. Developmental toxicity evaluation of Bendectin in CD rats. Teratology 1988;37:539–52.
4. McClure HM. Research and development studies relative to the experimental induction of oral facial malformation in the Rhesus monkey. No. 1 DE52452 Final report, May 1975–July 1981, August 1982. As cited in Brent RL. Bendectin: review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen. Reprod Toxicol 1995;9:337–49.
5. Hendrickx AG, Cukierski M, Prahalada S, Janos G, Rowland J. Evaluation of Bendectin embryotoxicity in nonhuman primates: I. Ventricular septal defects in prenatal macaques and baboon. Teratology 1985;32:179–89.
6. Hendrickx AG, Cukierski M, Prahalada S, Janos G, Booher S, Nyland T. Evaluation of Bendectin embryotoxicity in nonhuman primates: II. Double-blind study in term cynomolgus monkeys. Teratology 1985;32:191–4.
7. Korcok M. The Bendectin debate. Can Med Assoc J 1980;123:922–8.
8. Soverchia G, Perri PF. Two cases of malformations of a limb in infants of mothers treated with an antiemetic in a very early phase of pregnancy. Pediatr Med Chir 1981;3:97–9.
9. Donaldson GL, Bury RG. Multiple congenital abnormalities in a newborn boy associated with maternal use of fluphenazine enanthate and other drugs during pregnancy. Acta Paediatr Scand 1982;71:335–8.
10. Grodofsky MP, Wilmott RW. Possible association of use of Bendectin during early pregnancy and congenital lung hypoplasia. N Engl J Med 1984;311:732.
11. Fisher JE, Nelson SJ, Allen JE, Holsman RS. Congenital cystic adenomatoid malformation of the lung. A unique variant. Am J Dis Child 1982;136:1071–4.
12. Bracken MB, Berg A. Bendectin (Debendox) and congenital diaphragmatic hernia. Lancet 1983;1:586.
13. Golding J, Vivian S, Baldwin JA. Maternal anti-nauseants and clefts of lip and palate. Human Toxicol 1983;2:63–73.
14. Robison LL, Buckley JD, Daigle AE, Wells R, Benjamin D, Arthur DC, Hammond GD. Maternal drug use and risk of childhood nonlymphoblastic leukemia among offspring: an epidemiologic investigation implicating marijuana (a report from the Childrens Cancer Study Group). Cancer 1989;63:1904–11.
15. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977:474–5.
16. Ohga K, Yamanaka R, Kinumaki H, Awa S, Kobayashi N. Bendectin (Debendox) and congenital diaphragmatic hernia. Lancet 1983;1:930.
17. Eskenazi B, Bracken MB. Bendectin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol 1982;144:919–24.
18. Zierler S, Rothman KJ. Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy. N Engl J Med 1985;313:347–52.
19. Bendectin and pyloric stenosis. FDA Drug Bull 1983;13:14–5.
20. Mitchell AA, Schwingl PJ, Rosenberg L, Louik C, Shapiro S. Birth defects in relation to Bendectin use in pregnancy. II. Pyloric stenosis. Am J Obstet Gynecol 1983;147:737–42.
21. Aselton P, Jick H, Chentow SJ, Perera DR, Hunter JR, Rothman KJ. Pyloric stenosis and maternal Bendectin exposure. Am J Epidemiol 1984;120:251–6.
22. Pyloric stenosis. Buyse ML. ed. Birth Defects Encyclopedia. Volume II. Cambridge, MA:Blackwell Scientific Publications, 1990:1448.
23. Holmes LB. Teratogen update: Bendectin. Teratology 1983;27:277–81.
24. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and congenital malformations. Obstet Gynecol 1985;65:451–5.
25. Milkovich L, van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976;125:244–8.
26. Shapiro S, Heinonen OP, Siskind V, Kaufman DW, Monson RR, Slone D. Antenatal exposure to doxylamine succinate and dicyclomine hydrochloride (Bendectin) in relation to congenital malformations, perinatal mortality rate, birth weight, intelligence quotient score. Am J Obstet Gynecol 1977;128:480–5.
27. Rothman KJ, Flyer DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109:433–9.
28. Bunde CA, Bowles DM. A technique for controlled survey of case records. Curr Ther Res 1963;5:245–8.
29. Gibson GT, Collen DP, McMichael AJ, Hartshorne JM. Congenital anomalies in relation to the use of doxylamine/dicyclomine and other antenatal factors. An ongoing prospective study. Med J Aust 1981;1:410–4.
30. Correy JF, Newman NM. Debendox and limb reduction deformities. Med J Aust 1981;1:417–8.
31. Clarke M, Clayton DG. Safety of Debendox. Lancet 1981;2:659–60.
32. Harron DWG, Griffiths K, Shanks RG. Debendox and congenital malformations in Northern Ireland. Br Med J 1980;4:1379–81.
33. Smithells RW, Sheppard S. Teratogenicity testing in humans: a method demonstrating safety of Bendectin. Teratology 1978;17:31–5.
34. Morelock S, Hingson R, Kayne H, et al. Bendectin and fetal development: a study at Boston City Hospital. Am J Obstet Gynecol 1982;142:209–13.
35. Cordero JF, Oakley GP, Greenberg F, James LM. Is Bendectin a teratogen? JAMA 1981;245:2307–10.
36. Mitchell AA, Rosenberg L, Shapiro S, Slone D. Birth defects related to Bendectin use in pregnancy: I. Oral clefts and cardiac defects. JAMA 1981;245:2311–4.
37. Fleming DM, Knox JDE, Crombie DL. Debendox in early pregnancy and fetal malformation. Br Med J 1981;283:99–101.
38. Greenberg G, Inman WHW, Weatherall JAC, Adelstein AM, Haskey JC. Maternal drug histories and congenital abnormalities. Br Med J 1977;2:853–6.
39. Aselton PJ, Jick H. Additional follow-up of congenital limb disorders in relation to Bendectin use. JAMA 1983;250:33–4.
40. McCredie J, Kricker A, Elliott J, Forrest J. The innocent bystander: doxylamine/dicyclomine/pyridoxine and congenital limb defects. Med J Aust 1984;140:525–7.
41. Brent RR. Editorial. The Bendectin saga: another American tragedy. Teratology 1983;27:283–6.
42. Hughes DT, Cavanagh N. Chromosomal studies on children with phocomelia, exposed to Debendox during early pregnancy. Lancet 1983;2:399.
43. David TJ. Debendox does not cause the Poland anomaly. Arch Dis Child 1982;57:479–80.
44. Shiono PH, Klebanoff MA. Bendectin and human congenital malformations. Teratology 1989;40:151–5.
45. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiological studies. Drug Intell Clin Pharm 1988;22:813–24.
46. McKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendectin and birth defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994;50:27–37.
47. Brent RL. Bendectin: review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen. Reprod Toxicol 1995;9:337–49.
48. Newman SA. Bendectin—birth defects controversy. JAMA 1990;264:569.
49. Skolnick A. Bendectin—birth defects controversy. Reply. JAMA 1990;264:569–70.
50. Scialli AR. Editor's note. Reprod Toxicol 1999;13:239.
51. Newman SA. Dr. Brent and scientific debate. Reprod Toxicol 1999;13:241–4.
52. Brent RL. Response to Dr. Stuart Newman's commentary on an article entitled “Bendectin: review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen.” Reprod Toxicol 1999;13:245–53.
53. Newman SA. Response to Dr. Brent's commentary on “Dr. Brent and scientific debate.” Reprod Toxicol 1999;13:255–60.
54. Boneva RS, Moore CA, Botto L, Wong L-Y, Erickson JD. Nausea during pregnancy and congenital heart defects: a population-based case-control study. Am J Epidemiol 1999;149:717–25.
55. Ornstein M, Einarson A, Koren G. Bendectin/Diclectin for morning sickness: a Canadian follow-up of an American tragedy. Reprod Toxicol 1995;9:1–6.
56. Product information. Unisom SleepTabs. Pfizer Inc, 1999.

Continue reading here: Vaccine, Varicella Virus

Was this article helpful?

0 0