Original Article
701
Re-analysis of Safety Data Supporting Doxylamine Use for Nausea and Vomiting of Pregnancy Sarah Gregor1
1 Keenan Research Centre of the Li Ka Shing Knowledge Institute,
St Michael’s Hospital, Toronto, Ontario, Canada 2 Department of Family and Community Medicine, St Michael’s Hospital, Toronto, Ontario, Canada 3 Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
Navindra Persaud, MD, MSc, CCFP1,2,3 Address for correspondence Navindra Persaud, MD, MSc, CCFP, 80 Bond Street, Toronto, Ontario M5B 1X2, Canada (e-mail: [email protected]).
Am J Perinatol 2014;31:701–710.
Abstract
Keywords
► congenital malformations ► doxylamine ► nausea and vomiting of pregnancy ► drug safety
Antihistamines are commonly used to treat nausea and vomiting of pregnancy (NVP). We re-analyzed the 24 primary studies cited in a 1997 meta-analysis that concluded antihistamine use for NVP was safe as they had been studied in more than 200,000 participating women and the pooled odds ratio for congenital malformations was 0.76 (95% confidence interval [CI]: 0.60–0.94). Our analysis of this meta-analysis showed that 139,414 women were included in 22 original studies involving antihistamines, 129,108 of which were in studies involving doxylamine. In these studies, 23,485 women were exposed to antihistamines, 14,624 of which were exposed to doxylamine. The summary relative risk (cohort studies) and odds ratio (case–control studies) for congenital malformations from antihistamine exposure were 1.09 (95% CI: 1.01–1.18) and 1.04 (95% CI: 0.91–1.19), and for doxylamine exposure, the summary relative risk and odds ratio were 0.94 (95% CI: 0.80–1.10) and 1.07 (95% CI: 0.93–1.23), respectively. Although not a new systematic review, our re-analysis demonstrates that the safety data for antihistamines, and doxylamine in particular, are based on many fewer than 200,000 participating women and exposures, and that doxylamine use is not associated with a decreased risk of malformations as previously reported.
Diclectin (Duchesnay Inc., Blainville, Quebec, Canada) is commonly used to treat nausea and vomiting of pregnancy (NVP) in Canada.1,2 It contains 10 mg of pyridoxine (vitamin B6), an essential coenzyme for the metabolism of macromolecules, and 10 mg of doxylamine, an ethanolamine class antihistamine.3,4 Both components received the highest safety rating “A” in Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk by Briggs et al.3 The strength of the safety data is the basis for doxylamine’s status as the first-line pharmacological treatment of NVP in Canada while commonly used antihistamines such as dimenhydrinate or
diphenhydramine are recommended as second-line agents by the Society of Obstetricians and Gynecologists of Canada (SOGC).5,6 Doxylamine and pyridoxine, together with dicyclomine, an antispasmodic, were manufactured in the United States as Bendectin and in the United Kingdom as Debendox. They were voluntarily removed from the market amidst lawsuits alleging teratogenicity such as an increased risk of congenital limb defects.3 Controversy over the safety of doxylaminepyridoxine prompted several studies and systematic reviews. One commonly cited systematic review was conducted by Seto
received November 5, 2012 accepted after revision August 23, 2013 published online December 9, 2013
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1358772. ISSN 0735-1631.
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Jessica W. S. Chin, MD, BHSc (Hons)1
Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
et al in 1997.7 This review was reported to include 24 primary studies of antihistamine use during the first trimester of pregnancy in humans. According to Seto et al, a total of more than 200,000 women (not all exposed) were enrolled in these 24 studies. Some of these studies contained subsets of data for doxylamine exposure. The summary odds ratio for malformations associated with antihistamine use in the first trimester was reported as 0.76 (95% confidence interval [CI]: 0.60–0.94), suggesting that the use of antihistamines including doxylamine-pyridoxine is associated with a reduced risk of malformations.7 The Public Health Agency of Canada, referencing the Seto et al meta-analysis,7 states that “[Diclectin] has been studied in over 200,000 pregnant women and has not been shown to increase the risk of teratogenicity.”4 These findings have been cited as demonstrating the safety of antihistamines in general and doxylamine in particular8,9: “the safety of antihistamines (including doxylamine) in pregnancy was confirmed by a recent meta-analysis … involving more than 200,000 first trimester exposures; first trimester exposure to antihistamines revealed a slightly lower risk for major/minor malformations (pooled OR ¼ 0.76 [95% CI 0.60,0.94]).”10 The objective of this study was to determine the strength of the safety data supporting the use of doxylamine during pregnancy by reanalyzing the primary studies included in the Seto et al meta-analysis.7 The safety data of other antihistamines included in the Seto et al meta-analysis were also examined.
Methods We examined the primary studies included in the metaanalysis by Seto et al in 1997.7 The study type (case–control or cohort), medications used, types of malformations, and numbers of malformations in exposed and unexposed women were abstracted by two investigators independently (with discrepancies being resolved by a third) from each of the primary studies cited in the Seto et al meta-analysis.7 Data were abstracted for antihistamines in general as well as doxylamine in particular, if applicable, from the primary studies included in the Seto et al meta-analysis. These were then used to calculate the pooled odds ratio for case–control studies and the pooled relative risk for cohort studies by the MantelHaenszel method using Review Manager statistical software (RevMan version 5.2; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). Statistical heterogeneity was estimated using the I2 statistic. The original raw data were also compared with the data reported in the metaanalysis by Seto et al.7 We also examined the primary studies included in a recently published meta-analysis by Mazzotta and Magee (2000).11
Results We reviewed the 24 studies included in the meta-analysis by Seto et al. A table in that meta-analysis shows the raw data from 24 studies and a summary odds ratio for all studies combined.7 ►Table 1 shows the antihistamine exposure in each study and the respective study type. American Journal of Perinatology
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Exclusion of Articles in This Current Analysis Of the 24 articles in the Seto et al meta-analysis, two were excluded from this current analysis. The first article by Ayd (1972)12 is entitled “Haloperidol: Fifteen years of clinical experience” and does not contain data about the safety of antihistamines during pregnancy. The second article by Aselton and Jick (1983)13 was cited twice using two different reference numbers, 11 and 18, in the Seto et al meta-analysis, with different data presented in the two entries7 (►Table 2). Neither entry corresponds with the data from Aselton and Jick (1983).13
Major Discrepancies of Data Nine data sets were placed under the incorrect references in Table 3 of the Seto et al meta-analysis. For instance, primary abstraction of data from Aselton and Jick (1983)13 revealed that the actual data were placed under Gibson et al (1981)14 in the Seto et al meta-analysis.7 Similarly, the actual data for Bunde and Bowles (1963)15 were placed under Kullander and Källén (1976),16 Gibson et al (1981)14 under Jick et al (1981),17 Golding et al (1983) 18 under Greenberg et al (1977),19 Greenberg et al (1977)19 under Newman et al (1977),20 Jick et al (1981)17 under General Practitioner Research Group (1963),21 Newman et al (1977)20 under Smithells and Sheppard (1978),22 and Zierler and Rothman (1985)23 under the duplicate reference,18 Aselton and Jick (1983),13 in Table 3 of the Seto et al meta-analysis. In addition to the misplacement of data, other discrepancies were found between our abstracted data and those presented in the Seto et al meta-analysis7 (►Table 2). The data in Table 3 of the Seto et al meta-analysis7 for the nine primary studies by Aselton and Jick (1983),13 Heinonen et al (1977),24 Mellin and Katzenstein (1963),25 Milkovich and van den Berg (1976),26 Nelson and Forfar (1971),27 Rothman et al (1979),28 Golding et al (1983),18 Morelock et al (1982),29 and Bunde and Bowles (1963)15 did not correspond with those found in the primary reports. For instance, Heinonen et al reported a total of 2,787 malformations associated in the control (unexposed group) during the first 4 months of pregnancy,24 whereas the Seto et al meta-analysis abstracted 5,274.7
Types of Antihistamines Consumed A total of eight cohort and one case–control studies in the Seto et al meta-analysis7 examined the safety of antihistamines other than doxylamine ( ►Table 2). Four of the 11 cohort studies used in the Seto et al meta-analysis contained separate data for doxylamine where odds ratios for congenital malformations could be calculated for doxylamine relative to other antihistamines such as dimenhydrinate and meclizine (►Table 2). The data analyzed by Seto et al cannot be used to compare the safety of different antihistamines.
Other Medications Consumed In some studies, the use of antihistamines was not mutually exclusive and therefore some women were exposed to more than one type of antihistamines in addition to doxylamine
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702
Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
703
Author and year
Antihistamine exposure
Study type
Heinonen et al 197724
Doxylamine succinate
Cohort
Seto et al 199337
Brompheniramine
Cohort, matched pairs
Nora et al 196738
Antihistamines
Cohort
Mellin and Katzenstein 196325
Meclizine, pyridoxine, dimenhydrinate and cyclizine
Cohort
Milkovich and van den Berg 197626
Dicyclomine, doxylamine and pyridoxine
Cohort
Aselton and Jick 198313
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort
Fleming et al 198139
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort
Michaelis et al 198340
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort, matched pairs
Jick et al 198117
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort
General Practitioner Research Group 196321
Antihistamines
Cohort
Kullander and Källén 197616
Promethazine, prochlorperazine, diphenhydramine, meclozine
Cohort
Nelson and Forfar 197127
Antihistamines
Case–control, matched pairs
Eskenazi and Bracken 198241
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Morelock et al 198229
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Rothman et al 197928
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Zierler and Rothman 198523
Doxylamine-succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Gibson et al 198114
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Golding et al 198318
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Greenberg et al 197719
Doxylamine
Case–control
Newman et al 197720
Doxylamine-succinate, dicyclomine hydrochloride and pyridoxine
Case–control
Smithells and Sheppard 197822
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Bunde and Bowles 196315
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Ayd 197212
a
a
b
b
Aselton and Jick 198313 a
This reference is a review article and not a primary study. Duplicate entry of reference 12.
b
American Journal of Perinatology
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No. 8/2014
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Table 1 Malformations and medications used in the 24 studies in the meta-analysis by Seto et al (1997)7
American Journal of Perinatology
Vol. 31
Nora et al 1967
Mellin and Katzenstein 1963
Milkovich and van den Berg 1976
Aselton and Jick 1983
Fleming et al 1981
Michaelis et al 1983
Jick et al 1981
General Practitioner Research Group 1963
Kullander and Källén 1976
9 (25)
10 (26)
No. 8/2014
11 (13)
13 (39)
14 (40)
20 (17)
21 (21)
27 (16)
Nelson and Forfar 1971
Eskenazi and Bracken 1982
6 (27)
12 (41)
44
15
659
151
21
56
245
39
1,208
91
131
230
3
2
5,274
Control mal.
1,634
766
2,197
4,526
5,526
1,935
21,149
5,557
4,222
461
74
32
38,438
Control no mal.
2,415
1,077
4,436
6,837
7,456
3,948
22,977
6,509
6,305
797
118
68
50,282
Total
Same
4
99
26
679
491 70
17
2,231
856
2
24
18
1,362
614
14 2
1,880
63
1,090
5,733
Exposed no mal.
72
30
79
461
Exposedmal.
Same
Same
4,323
569
148
4,526
855
3,887
9,234
7,968
469
c
45,944
41,301
Control no mal.
454
885
Summary relative risk
652
20
5
56
19
4
c
343
285
236
Same
Same
3,169
2,787
Control mal.
Primary studiesb
1,369
5,753
661
661
6,837
1,748
5,255
10,205
10,205
798
50,282
50,282
Total
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78
145
2,207
2,231
24
11
1,607
1,939
589
847
1,749
71
39
33
6,319
Exposed no mal.
78
35
31
14
203
35
2
1
251
Exposedmal.
Seto et al meta-analysis7
Doxylamine
1.40
0.30
0.94
Antihistamines
1.09
0.96–2.05
0.10–0.86
0.80–1.10
1.01–1.18
0.80–1.18
0.97
Antihistamines
0.20–3.43
0.38–2.73
0.54–1.40
0.82
1.02
0.87
0.50–1.79
0.57–1.41
0.95
0.65–1.31 0.90
0.26–7.78 0.93
1.43
0.37–1.06
0.83–1.38
1.07
0.62
0.71–1.32
0.22–7.19
0.05–5.26
0.84–1.30
1.07–1.29
95% Confidence intervalb
0.96
1.25
0.50
1.05
1.18
(a) Relative riskb (b) Odds ratiob
Doxylamine
Promethazine, prochlorperazine, diphenhydramine, meclozine
Doxylamine
Antihistamines
Doxylamine
Doxylamine
Doxylamine, piperazine derivative, meclizine, triflupromazine, dimenhydrinate, chlorphenoxamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine, phenothiazine, prochlorperazine, meclizine, cyclizine, trimethobenzamide
Meclizine, dimenhydrinate, cyclizine
Antihistamines
Brompheniramine
Doxylamine
Antihistamines, antinauseants, phenothiazines
Medication exposure/nonexposureb
Re-analysis of Safety Data Supporting Doxylamine
(b) Case–control studies
Seto et al 1993
8 (38)
Heinonen et al 1977
Author and year
5 (37)
4 (24)
(a) Cohort studies
Study reference number in Seto et al meta-analysisa
Table 2 Comparison of data presented in the Seto et al meta-analysis (1997)7 with raw data abstracted from the referenced primary studies for (a) cohort studies, (b) case–control studies, (c) the two excluded studies, and (d) total number of women involved
704 Chin et al.
Morelock et al 1982
Rothman et al 1979
Zierler and Rothman 1985
Gibson et al 1981
Golding et al 1983
Greenberg et al 1977
Newman et al 1977
Smithells and Sheppard 1978
Bunde and Bowles 1963
15 (29)
16 (28)
17 (23)
19 (14)
22 (18)
23 (19)
24 (20)
25 (22)
26 (15)
Aselton andJick 1983
18 (13)
–
19,307
240
9,263
31
70
760
184
24
4
366
93
162
Control mal.
–
125,658
607
18,339
1,682
6,671
748
398
57
3,886
1,208
1,222
4,323
Control no mal.
–
174,568
1,020
32,244
3,426
7,933
1,672
603
661
5,254
1,644
1,690
5,196
Total
508
1,116
e
d
11
27
6
76
12
78
52
24
8
Exposedmal.
14,116
22,369
e
d
2,207
1,595
1,186
88
9
1,607
121
46
367
Exposed no mal.
7,402
8,314
e
d
2,197
644
6,671
748
398
5,526
607
1,208
1,285
Control no mal.
10,7082
107,615
e
d
Summary odds ratio
21
8
70
760
184
245
240
366
30
Control mal.
Primary studiesb
12,9108
139,414
e
d
4,436
2,274
7,933
1,672
603
7,456
1,020
1,644
1,690
Total
–
–
–
–
–
–
–
1.07
–
1.04
Antihistamines
0.52
1.36
0.48
0.85
2.88
1.09
1.09
1.72
0.93
(a) Relative riskb (b) Odds ratiob
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Medication exposure/nonexposureb
–
–
–
–
0.93–1.23
0.91–1.19
0.25–1.08
0.62–3.02
0.21–1.11
0.62–1.17
1.19–6.97
0.84–1.42
0.76–1.55
1.04–2.86
0.42–2.05
95% Confidence intervalb
American Journal of Perinatology
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Abbreviation: mal., malformation. Notes: The numbers presented under the Seto et al meta-analysis heading are stated to represent exposure/nonexposure to antihsitamines.7 The numbers presented under the primary studies heading are raw data abstracted from the original studies. Data are presented for antihistamines and/or doxylamine if such can be abstracted from the original studies. a The numbers in parentheses are reference numbers used in this article. b The data were extracted from primary studies and calculations were performed for the re-analysis in this current study. c The number of unexposed women used in this re-analysis was determined to be 3,891, although both 3,891 and 3,890 were reported in the original primary study. d This reference is a review article and not a primary study. e Duplicate entry of reference 12.
27,142 –
2,461 –
121
3,207
1,685
1,186
88
9
561
1,362
46
344
679
Exposed no mal.
Total (doxylamine)
52
1,435
28
6
76
12
19
2
24
31
32
Exposedmal.
Seto et al meta-analysis7
Total (antihistamines)
(d) Total number of women involved
Ayd 1972
7 (12)
(c) Excluded studies
Author and year
Study reference number in Seto et al meta-analysisa
Table 2 (Continued)
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Table 3 A comparison of Mazzotta and Magee11 and Seto et al7 meta-analyses Seto et al7 Odds ratio (95% CI)
Mazzotta and Magee11 Relative risk (95% CI)
196315
0.90 (0.54–1.51)
0.52 (0.25–1.08)
General Practitioner Research Group
1963
21
0.87 (0.54–1.41)
0.81 (0.19–3.39)
Mellin and Katzenstein
196325
0.99 (0.64–1.53)
Study not of doxylaminea
Nora et al
196738
1.26 (0.20–7.89)
Study not of doxylaminea
Nelson and Forfar
197127
0.52 (0.30–0.92)
Study not of doxylaminea
Kullander and Källén
197616
0.52 (0.25–1.08)
Study not of doxylaminea
1976
26
3.74 (2.98–4.69)
Not included
1977
19
2.88 (1.19–6.97)
0.92 (0.77–1.09)
Heinonen et al
1977
24
0.29 (0.25–0.33)
0.97 (0.77–1.24)
Newman et al
197720
0.85 (0.62–1.17)
0.48 (0.21–1.11)
1978
22
0.48 (0.21–1.11)
1.56 (0.71–3.43)
Rothman et al
1979
28
1.18 (0.78–1.81)
Not included
Michaelis et al
198031
Not included
1.37 (0.86–2.16)
Fleming et al
198139
0.92 (0.64–1.33)
0.81 (0.40–1.62)
1981
14
1.43 (0.26–7.80)
1.09 (0.85–1.40)
Jick et al
1981
17
1.09 (0.84–1.42)
0.87 (0.54–1.40)
Eskenazi and Bracken
198241
1.40 (0.96–2.05)
1.25 (0.98–1.60)
1982
29
1.26 (0.85–1.85)
0.94 (0.43–2.02)
Aselton and Jick
1983
13
1.01 (0.57–1.78)
Not included
Golding et al
198318
0.08 (0.04–0.16)
Not included
1983
40
0.90 (0.56–1.42)
Not included
1985
33
Not included
1.25 (0.82–1.90)
Zierler and Rothman
1985
23
1.72 (1.04–2.86)
Not included
Shiono
198932
Not included
1.02 (0.77–1.36)
Erickson
199134
Not included
0.96 (0.90–1.01)
0.48 (0.04–5.61)
Study not of doxylaminea
0.76 (0.60–0.94)
0.98 (0.93–1.03)
Author
Year
Bunde and Bowles
Milkovich and van den Berg Greenberg et al
Smithells and Sheppard
Gibson et al
Morelock et al
Michaelis et al Aselton et al
Seto et al
1993
37
Pooled
Notes: Relative risks reported in the Mazzotta and Magee’s30 meta-analysis pertain to congenital malformations associated with doxylamine exposure. Odds ratios were not reported for individual studies in the Seto et al meta-analysis.7 Raw data as presented in the table (Seto et al meta-analysis on malformation rates in antihistamine-exposed/unexposed women) were used to calculate odds ratios and 95% CI using RevMan. a “Study not of doxylamine” denotes studies that do not contain specific data on doxylamine exposure.
during the first trimester. In addition, the consumption of other medications was not controlled for and women in either the doxylamine “exposed” or “unexposed” group might have taken other types of medications including medications that are now recognized as teratogens. One of the primary studies used in the Seto et al meta-analysis was a cohort study conducted by Heinonen et al (1977).24 As the largest study with 50,282 participating women, it evaluated many drugs including doxylamine succinate used in the first 4 months of pregnancy and their relations to malformations.
Malformations Examined The definition of malformations was not uniform across studies. Although some studies included both major and American Journal of Perinatology
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minor malformations, other studies excluded malformations considered to be minor by the studies’ researchers such as syndactyly and hypospadias.17
Sample Size, Relative Risk, and Odds Ratio In our current analysis, a total of 139,414 women were involved in 22 of the 24 articles used in the Seto et al metaanalysis (►Table 2). This differs from the reported sample size of “over 200,000 women” in the Seto et al meta-analysis.7 We found that 129,108 of the 139,414 women were in studies involving doxylamine. In all 22 eligible studies, 23,485 women had exposure to antihistamines and 14,624 women had exposure to doxylamine (►Table 2). The summary relative risk for
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706
Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
707
malformations associated with doxylamine use in the seven cohort studies with applicable doxylamine data was 0.94 (95% CI: 0.80–1.10) (►Table 2a and ►Fig. 1). There was no statistical heterogeneity (I2 ¼ 0). The summary odds ratio was 1.07 (95% CI: 0.93–1.23) in the 10 case–control studies with doxylamine applicable data (►Table 2b and ►Fig. 2). There was moderate heterogeneity (I2 ¼ 55%). The summary relative risk for malformations associated with antihistamine
use was 1.09 (95% CI: 1.01–1.18) in the 11 cohort studies (►Table 2a and ►Fig. 3) with no statistical heterogeneity (I2 ¼ 0), whereas the summary odds ratio was 1.04 (95% CI: 0.91–1.19) in the 11 case–control studies (►Table 2b and ►Fig. 4) with moderate statistical heterogeneity (I2 ¼ 61%). In comparison, the summary odds ratio of major malformations associated with first-trimester antihistamine exposure reported in the Seto et al meta-analysis was lower at
Fig. 2 Summary analysis (odds ratio) for malformations associated with first-trimester doxylamine use in 10 case–control studies. CI, confidence interval; M-H, Mantel-Haenszel.
Fig. 3 Summary analysis (relative risk) for malformations associated with first-trimester antihistamine use in 11 cohort studies. CI, confidence interval; GPRG, General Practitioner Research Group; M-H, Mantel-Haenszel.
American Journal of Perinatology
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Fig. 1 Summary analysis (relative risk) for malformations associated with first-trimester doxylamine use in seven cohort studies.CI, confidence interval; GPRG, General Practitioner Research Group; M-H, Mantel-Haenszel.
Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
Fig. 4 Summary analysis (odds ratio) for malformations associated with first-trimester antihistamine use in 11 case–control studies. CI, confidence interval; M-H, Mantel-Haenszel.
a value of 0.76 (95% CI: 0.60–0.94).7 The relative risk/odds ratio was not reported for each individual study in Table 3 of the Seto et al meta-analysis. Only the summary odds ratio was reported in the text of the article.
Quality of Primary Studies Included in the Seto et al Meta-analysis The primary studies included in the Seto et al meta-analysis with the lowest odds ratios for malformations were the oldest studies and they employed questionable methodologies. In the General Practitioner Clinical Trials, physicians were invited to provide information about patients seen during a prospective 9-month period, but they were also given the option of including patients seen during the previous 6 months.21 The number of patients recruited in each period was not reported, so it is unclear if the retrospective group introduced a selection bias. In the study by Bunde and Bowles (1963), 21 physicians identified to prescribe Bendectin frequently were selected by the Wm. S. Merrell Company (Cincinnati, OH) which manufactured the medication.15 These physicians were asked to complete questionnaires about the use of medications among pregnant patients in their practice. The odds ratio for birth defects associated with Bendectin exposure from this study was 0.52 (95% CI: 0.25– 1.1) which is substantially lower than those found in subsequent studies that employed more conventional methodologies (►Fig. 2).
The More Recent Meta-analysis on Doxylamine Mazzotta and Magee (2000)11 adapted McKeigue et al’s metaanalysis (1994)30 and published another review that included the same 15 primary studies used by McKeigue et al, except one study by Milkovich and van den Berg (1976).26 With a pooled relative risk of 0.98 (95% CI: 0.93–1.03), Mazzotta and Magee concluded that the first-trimester to doxylamine is not associated with an increased risk of major or minor congenital malformations.11 The meta-analyses by Seto et al7 and by Mazzotta and Magee11 included different primary studies (4 of the 16 studies in Mazzotta and Magee’s review were not included in Seto et al’s meta-analysis and 6 of the 22 eligible studies in American Journal of Perinatology
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Seto et al’s meta-analysis were excluded in McKeigue et al’s review30) (►Table 3).
Discussion The Seto et al meta-analysis was performed to examine the safety of antihistamines in general and some of the studies included subsets of data specifically for doxylamine.7 This allowed for the examination of doxylamine’s safety for NVP. The strength of safety data for doxylamine has been overstated. This is important because recommendations for doxylamine are based on the strength of safety data in comparison to other commonly used agents.5 Although our reanalysis and the Seto et al meta-analysis did not identify a strong association between doxylamine use and malformations, doxylamine has not been studied in as many patients as claimed in the Seto et al meta-analysis,7 and our pooled odds ratio for malformations is significantly different (nonoverlapping confidence intervals) from that reported in the Seto et al meta-analysis.7 The Seto et al meta-analysis stated that the “analysis included over 200,000 investigated women in 24 different studies, and therefore it has an unprecedented power to reject the suggestion of teratogenic potential of this class of drugs.”7 Diclectin is recommended as the first-line pharmacological agent for NVP in Canada based on the strength of the safety evidence.5 The Public Health Agency of Canada, referencing the Seto et al meta-analysis only,7 states that “[Diclectin] has been studied in over 200 000 pregnant women and has not been shown to increase the risk of teratogenicity.”4 Our reanalysis identified a total of 139,414 women in reports about the safety of antihistamines and 129,108 in reports about the safety of doxylamine. In these studies, 23,485 women were exposed to antihistamines and 14,624 were exposed to doxylamine. The strength of the safety data for doxylamine relative to other antihistamines is less than previously claimed. Data about other commonly used antihistamines were also provided by some of the primary studies used in the Seto et al meta-analysis7 (►Table 2). For example, the largest cohort study of 50,282 women by Heinonen et al (1977) provides
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Re-analysis of Safety Data Supporting Doxylamine
amine-pyridoxine is associated with an increased risk of malformations the evidence for the safety of doxylamine is not as strong as previously claimed. This current analysis provides a more accurate presentation of the safety data in the primary studies used by Seto et al7 for antihistamines including doxylamine. This should be taken into consideration as recommendations for NVP treatment are revised.
Acknowledgments N.P. is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research and by the Department of Family and Community Medicine, St Michael’s Hospital, Toronto, Canada.
References 1 Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of
2
3
4
5
6
7
8
9 10
11
Conclusion Our current analysis, albeit not a new systematic review, illustrates that the safety of doxylamine use for NVP in the first trimester has been overstated by the Seto et al metaanalysis. As discussed by Matthews et al in their 2010 Cochrane review on the effectiveness and safety on all interventions for NVP, there is currently a lack of consistent outcome measurement and high-quality evidence in the literature.36 As such their review “would not support [the] simplistic conclusion” that “Bendectin/Diclectin, antihistamine blockers, and phenothiazines as a group are safe and effective for treatment” as suggested by others.11 Although doxylamine has been studied in a large number of women and our revised odds ratio does not demonstrate that doxyl-
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12 13 14
15 16 17
nausea and vomiting during pregnancy. Br J Gen Pract 1993; 43(371):245–248 Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy: a prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 2000;182(4):931–937 Briggs G, Freeman RK, Yaffe SJ. Doxylamine. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risks. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011:4527 Public Health Agency of Canada. Statement on Pregnancy and Travel; 2010. Available at: http://www.phac-aspc.gc.ca/publicat/ ccdr-rmtc/10vol36/acs-2/index-eng.php. Accessed May 17, 2012 Arsenault MY, Lane CA, MacKinnon CJ, et al. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can 2002; 24(10):817–831, quiz 832–833 Einarson A, Maltepe C, Boskovic R, Koren G. Treatment of nausea and vomiting in pregnancy: an updated algorithm. Can Fam Physician 2007;53(12):2109–2111 Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol 1997;14(3):119–124 Kar S, Krishnan A, Preetha K, Mohankar A. A review of antihistamines used during pregnancy. J Pharmacol Pharmacother 2012; 3(2):105–108 So M, Bozzo P, Inoue M, Einarson A. Safety of antihistamines during pregnancy and lactation. Can Fam Physician 2010;56(5):427–429 Magee LA, Mazzotta P, Koren G. Evidence-based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP). Am J Obstet Gynecol 2002;186(5, Suppl Understanding ):S256–S261 Mazzotta P, Magee LA. A risk-benefit assessment of pharmacological and non-pharmacological treatments for nausea and vomiting of pregnancy. Drugs 2000;59:781–800 Ayd FJ Jr. Haloperidol: fifteen years of clinical experience. Dis Nerv Syst 1972;33(7):459–469 Aselton PJ, Jick H. Additional follow-up of congenital limb disorders in relation to Bendectin use. JAMA 1983;250(1):33–34 Gibson GT, Colley 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(8):410–414 Bunde CA, Bowles DM. A technique for controlled survey of case records. Curr Ther Res Clin Exp 1963;5:245–248 Kullander S, Källén B. A prospective study of drugs and pregnancy. II. Anti-emetic drugs. Acta Obstet Gynecol Scand 1976;55(2):105–111 Jick H, Holmes LB, Hunter JR, Madsen S, Stergachis A. Firsttrimester drug use and congenital disorders. JAMA 1981;246(4): 343–346 American Journal of Perinatology
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safety data for dimenhydrinate and other antihistamines,24 and thus could not be considered a study of doxylamine. There was also a lack of adjustment for confounding factors such as exposure to other potential teratogens in the primary studies. The Seto et al meta-analysis reported an odds ratio of 0.76 (95% CI: 0.60–0.94) for antihistamine use in the first trimester,7 and this is different from our recalculated odds ratio of 1.04 (95% CI: 0.91–1.19). Mazzotta and Magee reported a pooled relative risk of 0.98 (95% CI: 0.93–1.03) and concluded that firsttrimester to doxylamine is not associated with an increased risk of major or minor congenital malformations.11 Mazzotta and Magee did not include the same primary studies in their meta-analysis as Seto et al. The study by Michaelis et al (1980)31 might have been excluded by Seto et al7 as it was published in German. The study by Shiono and Klebanoff (1989)32 did not present an overall “exposed” and “unexposed” rates of outcomes which might have led to its exclusion by Seto et al.7 It is unclear why the two studies by Aselton et al (1985)33 and Erickson (1991)34 were excluded from the Seto et al meta-analysis, 7 as they appeared to meet the inclusion and exclusion criteria set by Seto et al. On the basis of a pooled odds ratio of 0.76 (95% CI: 0.60– 0.94) in the Seto et al meta-analysis, the authors also concluded that antihistamines including doxylamine for NVP may be associated with a protective effect against teratogenic risk.7 Some researchers have taken the pooled odds ratio in the Seto et al meta-analysis and its conclusion7 to indicate that antihistamines including doxylamine may prevent malformations. Fejzo et al (2008) stated that “if treated early, severe nausea may be associated with a protective effect against major malformations” referencing the Seto et al meta-analysis.35 The SOGC guidelines on the management of NVP also cited the Seto et al meta-analysis7 and stated that “data have actually shown a slightly reduced incidence of major and minor malformations with first-trimester exposure to various antihistamines.”5 The more recent meta-analysis by Mazzotta and Magee (2000)11 was not cited for evidence of safety by the SOGC. Our re-analysis together with the meta-analyses by McKeigue et al30 as well as Mazzotta and Magee11 did not show that doxylamine reduces the risk of congenital malformations.
Chin et al.
Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
18 Golding J, Vivian S, Baldwin JA. Maternal anti-nauseants and clefts
30 McKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendectin and birth
of lip and palate. Hum Toxicol 1983;2(1):63–73 Greenberg G, Inman WHW, Weatherall JAC, Adelstein AM, Haskey JC. Maternal drug histories and congenital abnormalities. BMJ 1977;2(6091):853–856 Newman NM, Correy JF, Dudgeon GI. A survey of congenital abnormalities and drugs in a private practice. Aust N Z J Gynaecol 1977;17:156–159 General Practitioner Research Group. General Practitioner Clinical Trials: DRUGS IN PREGNANCY SURVEY. Practitioner 1963;191:775–780 Smithells RW, Sheppard S. Teratogenicity testing in humans: a method demonstrating safety of bendectin. Teratology 1978; 17(1):31–35 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(6):347–352 Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton MA: PSG Publishing; 1977 Mellin G, Katzenstein M. Meclozine and fetal abnormalities. Lancet 1963;26:222–223 Milkovich L, van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976;125(2): 244–248 Nelson MM, Forfar JO. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. BMJ 1971;1(5748):523–527 Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109(4):433–439 Morelock S, Hingson R, Kayne H, et al. Bendectin and fetal development. A study of Boston City Hospital. Am J Obstet Gynecol 1982;142(2):209–213
defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994;50(1):27–37 Michaelis J, Gluck E, Michaelis H, et al. Does Lenotan have teratogenic effects? Dtsch Arzt 1980;23:1527–1529 Shiono PH, Klebanoff MA. Bendectin and human congenital malformations. Teratology 1989;40(2):151–155 Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. Firsttrimester drug use and congenital disorders. Obstet Gynecol 1985;65(4):451–455 Erickson JD. Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study. Teratology 1991;43(1):41–51 Fejzo MS, Ingles SA, Wilson M, et al. High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals. Eur J Obstet Gynecol Reprod Biol 2008;141(1):13–17 Matthews A, Dowswell T, Haas DM, Doyle M, O’Mathúna DP. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2010(9, Issue 9)CD007575 Seto A, Einarson T, Koren G. Evaluation of brompheniramine safety in pregnancy. Reprod Toxicol 1993;7(4):393–395 Nora JJ, Nora AH, Sommerville RJ, Hill RM, McNamara DG. Maternal exposure to potential teratogens. JAMA 1967;202(12): 1065–1069 Fleming DM, Knox JDE, Crombie DL. Debendox in early pregnancy and fetal malformation. Br Med J (Clin Res Ed) 1981;283(6284):99–101 Michaelis J, Michaelis H, Glück E, Koller S. Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformations. Teratology 1983;27(1):57–64 Eskenazi B, Bracken MB. Bendectin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol 1982;144(8):919–924
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Re-analysis of Safety Data Supporting Doxylamine Use for Nausea and Vomiting of Pregnancy Sarah Gregor1
1 Keenan Research Centre of the Li Ka Shing Knowledge Institute,
St Michael’s Hospital, Toronto, Ontario, Canada 2 Department of Family and Community Medicine, St Michael’s Hospital, Toronto, Ontario, Canada 3 Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
Navindra Persaud, MD, MSc, CCFP1,2,3 Address for correspondence Navindra Persaud, MD, MSc, CCFP, 80 Bond Street, Toronto, Ontario M5B 1X2, Canada (e-mail: [email protected]).
Am J Perinatol 2014;31:701–710.
Abstract
Keywords
► congenital malformations ► doxylamine ► nausea and vomiting of pregnancy ► drug safety
Antihistamines are commonly used to treat nausea and vomiting of pregnancy (NVP). We re-analyzed the 24 primary studies cited in a 1997 meta-analysis that concluded antihistamine use for NVP was safe as they had been studied in more than 200,000 participating women and the pooled odds ratio for congenital malformations was 0.76 (95% confidence interval [CI]: 0.60–0.94). Our analysis of this meta-analysis showed that 139,414 women were included in 22 original studies involving antihistamines, 129,108 of which were in studies involving doxylamine. In these studies, 23,485 women were exposed to antihistamines, 14,624 of which were exposed to doxylamine. The summary relative risk (cohort studies) and odds ratio (case–control studies) for congenital malformations from antihistamine exposure were 1.09 (95% CI: 1.01–1.18) and 1.04 (95% CI: 0.91–1.19), and for doxylamine exposure, the summary relative risk and odds ratio were 0.94 (95% CI: 0.80–1.10) and 1.07 (95% CI: 0.93–1.23), respectively. Although not a new systematic review, our re-analysis demonstrates that the safety data for antihistamines, and doxylamine in particular, are based on many fewer than 200,000 participating women and exposures, and that doxylamine use is not associated with a decreased risk of malformations as previously reported.
Diclectin (Duchesnay Inc., Blainville, Quebec, Canada) is commonly used to treat nausea and vomiting of pregnancy (NVP) in Canada.1,2 It contains 10 mg of pyridoxine (vitamin B6), an essential coenzyme for the metabolism of macromolecules, and 10 mg of doxylamine, an ethanolamine class antihistamine.3,4 Both components received the highest safety rating “A” in Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk by Briggs et al.3 The strength of the safety data is the basis for doxylamine’s status as the first-line pharmacological treatment of NVP in Canada while commonly used antihistamines such as dimenhydrinate or
diphenhydramine are recommended as second-line agents by the Society of Obstetricians and Gynecologists of Canada (SOGC).5,6 Doxylamine and pyridoxine, together with dicyclomine, an antispasmodic, were manufactured in the United States as Bendectin and in the United Kingdom as Debendox. They were voluntarily removed from the market amidst lawsuits alleging teratogenicity such as an increased risk of congenital limb defects.3 Controversy over the safety of doxylaminepyridoxine prompted several studies and systematic reviews. One commonly cited systematic review was conducted by Seto
received November 5, 2012 accepted after revision August 23, 2013 published online December 9, 2013
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1358772. ISSN 0735-1631.
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Jessica W. S. Chin, MD, BHSc (Hons)1
Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
et al in 1997.7 This review was reported to include 24 primary studies of antihistamine use during the first trimester of pregnancy in humans. According to Seto et al, a total of more than 200,000 women (not all exposed) were enrolled in these 24 studies. Some of these studies contained subsets of data for doxylamine exposure. The summary odds ratio for malformations associated with antihistamine use in the first trimester was reported as 0.76 (95% confidence interval [CI]: 0.60–0.94), suggesting that the use of antihistamines including doxylamine-pyridoxine is associated with a reduced risk of malformations.7 The Public Health Agency of Canada, referencing the Seto et al meta-analysis,7 states that “[Diclectin] has been studied in over 200,000 pregnant women and has not been shown to increase the risk of teratogenicity.”4 These findings have been cited as demonstrating the safety of antihistamines in general and doxylamine in particular8,9: “the safety of antihistamines (including doxylamine) in pregnancy was confirmed by a recent meta-analysis … involving more than 200,000 first trimester exposures; first trimester exposure to antihistamines revealed a slightly lower risk for major/minor malformations (pooled OR ¼ 0.76 [95% CI 0.60,0.94]).”10 The objective of this study was to determine the strength of the safety data supporting the use of doxylamine during pregnancy by reanalyzing the primary studies included in the Seto et al meta-analysis.7 The safety data of other antihistamines included in the Seto et al meta-analysis were also examined.
Methods We examined the primary studies included in the metaanalysis by Seto et al in 1997.7 The study type (case–control or cohort), medications used, types of malformations, and numbers of malformations in exposed and unexposed women were abstracted by two investigators independently (with discrepancies being resolved by a third) from each of the primary studies cited in the Seto et al meta-analysis.7 Data were abstracted for antihistamines in general as well as doxylamine in particular, if applicable, from the primary studies included in the Seto et al meta-analysis. These were then used to calculate the pooled odds ratio for case–control studies and the pooled relative risk for cohort studies by the MantelHaenszel method using Review Manager statistical software (RevMan version 5.2; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). Statistical heterogeneity was estimated using the I2 statistic. The original raw data were also compared with the data reported in the metaanalysis by Seto et al.7 We also examined the primary studies included in a recently published meta-analysis by Mazzotta and Magee (2000).11
Results We reviewed the 24 studies included in the meta-analysis by Seto et al. A table in that meta-analysis shows the raw data from 24 studies and a summary odds ratio for all studies combined.7 ►Table 1 shows the antihistamine exposure in each study and the respective study type. American Journal of Perinatology
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Exclusion of Articles in This Current Analysis Of the 24 articles in the Seto et al meta-analysis, two were excluded from this current analysis. The first article by Ayd (1972)12 is entitled “Haloperidol: Fifteen years of clinical experience” and does not contain data about the safety of antihistamines during pregnancy. The second article by Aselton and Jick (1983)13 was cited twice using two different reference numbers, 11 and 18, in the Seto et al meta-analysis, with different data presented in the two entries7 (►Table 2). Neither entry corresponds with the data from Aselton and Jick (1983).13
Major Discrepancies of Data Nine data sets were placed under the incorrect references in Table 3 of the Seto et al meta-analysis. For instance, primary abstraction of data from Aselton and Jick (1983)13 revealed that the actual data were placed under Gibson et al (1981)14 in the Seto et al meta-analysis.7 Similarly, the actual data for Bunde and Bowles (1963)15 were placed under Kullander and Källén (1976),16 Gibson et al (1981)14 under Jick et al (1981),17 Golding et al (1983) 18 under Greenberg et al (1977),19 Greenberg et al (1977)19 under Newman et al (1977),20 Jick et al (1981)17 under General Practitioner Research Group (1963),21 Newman et al (1977)20 under Smithells and Sheppard (1978),22 and Zierler and Rothman (1985)23 under the duplicate reference,18 Aselton and Jick (1983),13 in Table 3 of the Seto et al meta-analysis. In addition to the misplacement of data, other discrepancies were found between our abstracted data and those presented in the Seto et al meta-analysis7 (►Table 2). The data in Table 3 of the Seto et al meta-analysis7 for the nine primary studies by Aselton and Jick (1983),13 Heinonen et al (1977),24 Mellin and Katzenstein (1963),25 Milkovich and van den Berg (1976),26 Nelson and Forfar (1971),27 Rothman et al (1979),28 Golding et al (1983),18 Morelock et al (1982),29 and Bunde and Bowles (1963)15 did not correspond with those found in the primary reports. For instance, Heinonen et al reported a total of 2,787 malformations associated in the control (unexposed group) during the first 4 months of pregnancy,24 whereas the Seto et al meta-analysis abstracted 5,274.7
Types of Antihistamines Consumed A total of eight cohort and one case–control studies in the Seto et al meta-analysis7 examined the safety of antihistamines other than doxylamine ( ►Table 2). Four of the 11 cohort studies used in the Seto et al meta-analysis contained separate data for doxylamine where odds ratios for congenital malformations could be calculated for doxylamine relative to other antihistamines such as dimenhydrinate and meclizine (►Table 2). The data analyzed by Seto et al cannot be used to compare the safety of different antihistamines.
Other Medications Consumed In some studies, the use of antihistamines was not mutually exclusive and therefore some women were exposed to more than one type of antihistamines in addition to doxylamine
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Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
703
Author and year
Antihistamine exposure
Study type
Heinonen et al 197724
Doxylamine succinate
Cohort
Seto et al 199337
Brompheniramine
Cohort, matched pairs
Nora et al 196738
Antihistamines
Cohort
Mellin and Katzenstein 196325
Meclizine, pyridoxine, dimenhydrinate and cyclizine
Cohort
Milkovich and van den Berg 197626
Dicyclomine, doxylamine and pyridoxine
Cohort
Aselton and Jick 198313
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort
Fleming et al 198139
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort
Michaelis et al 198340
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort, matched pairs
Jick et al 198117
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Cohort
General Practitioner Research Group 196321
Antihistamines
Cohort
Kullander and Källén 197616
Promethazine, prochlorperazine, diphenhydramine, meclozine
Cohort
Nelson and Forfar 197127
Antihistamines
Case–control, matched pairs
Eskenazi and Bracken 198241
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Morelock et al 198229
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Rothman et al 197928
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Zierler and Rothman 198523
Doxylamine-succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Gibson et al 198114
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Golding et al 198318
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Greenberg et al 197719
Doxylamine
Case–control
Newman et al 197720
Doxylamine-succinate, dicyclomine hydrochloride and pyridoxine
Case–control
Smithells and Sheppard 197822
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Bunde and Bowles 196315
Doxylamine succinate, dicyclomine hydrochloride and pyridoxine hydrochloride
Case–control
Ayd 197212
a
a
b
b
Aselton and Jick 198313 a
This reference is a review article and not a primary study. Duplicate entry of reference 12.
b
American Journal of Perinatology
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No. 8/2014
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Table 1 Malformations and medications used in the 24 studies in the meta-analysis by Seto et al (1997)7
American Journal of Perinatology
Vol. 31
Nora et al 1967
Mellin and Katzenstein 1963
Milkovich and van den Berg 1976
Aselton and Jick 1983
Fleming et al 1981
Michaelis et al 1983
Jick et al 1981
General Practitioner Research Group 1963
Kullander and Källén 1976
9 (25)
10 (26)
No. 8/2014
11 (13)
13 (39)
14 (40)
20 (17)
21 (21)
27 (16)
Nelson and Forfar 1971
Eskenazi and Bracken 1982
6 (27)
12 (41)
44
15
659
151
21
56
245
39
1,208
91
131
230
3
2
5,274
Control mal.
1,634
766
2,197
4,526
5,526
1,935
21,149
5,557
4,222
461
74
32
38,438
Control no mal.
2,415
1,077
4,436
6,837
7,456
3,948
22,977
6,509
6,305
797
118
68
50,282
Total
Same
4
99
26
679
491 70
17
2,231
856
2
24
18
1,362
614
14 2
1,880
63
1,090
5,733
Exposed no mal.
72
30
79
461
Exposedmal.
Same
Same
4,323
569
148
4,526
855
3,887
9,234
7,968
469
c
45,944
41,301
Control no mal.
454
885
Summary relative risk
652
20
5
56
19
4
c
343
285
236
Same
Same
3,169
2,787
Control mal.
Primary studiesb
1,369
5,753
661
661
6,837
1,748
5,255
10,205
10,205
798
50,282
50,282
Total
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78
145
2,207
2,231
24
11
1,607
1,939
589
847
1,749
71
39
33
6,319
Exposed no mal.
78
35
31
14
203
35
2
1
251
Exposedmal.
Seto et al meta-analysis7
Doxylamine
1.40
0.30
0.94
Antihistamines
1.09
0.96–2.05
0.10–0.86
0.80–1.10
1.01–1.18
0.80–1.18
0.97
Antihistamines
0.20–3.43
0.38–2.73
0.54–1.40
0.82
1.02
0.87
0.50–1.79
0.57–1.41
0.95
0.65–1.31 0.90
0.26–7.78 0.93
1.43
0.37–1.06
0.83–1.38
1.07
0.62
0.71–1.32
0.22–7.19
0.05–5.26
0.84–1.30
1.07–1.29
95% Confidence intervalb
0.96
1.25
0.50
1.05
1.18
(a) Relative riskb (b) Odds ratiob
Doxylamine
Promethazine, prochlorperazine, diphenhydramine, meclozine
Doxylamine
Antihistamines
Doxylamine
Doxylamine
Doxylamine, piperazine derivative, meclizine, triflupromazine, dimenhydrinate, chlorphenoxamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine, phenothiazine, prochlorperazine, meclizine, cyclizine, trimethobenzamide
Meclizine, dimenhydrinate, cyclizine
Antihistamines
Brompheniramine
Doxylamine
Antihistamines, antinauseants, phenothiazines
Medication exposure/nonexposureb
Re-analysis of Safety Data Supporting Doxylamine
(b) Case–control studies
Seto et al 1993
8 (38)
Heinonen et al 1977
Author and year
5 (37)
4 (24)
(a) Cohort studies
Study reference number in Seto et al meta-analysisa
Table 2 Comparison of data presented in the Seto et al meta-analysis (1997)7 with raw data abstracted from the referenced primary studies for (a) cohort studies, (b) case–control studies, (c) the two excluded studies, and (d) total number of women involved
704 Chin et al.
Morelock et al 1982
Rothman et al 1979
Zierler and Rothman 1985
Gibson et al 1981
Golding et al 1983
Greenberg et al 1977
Newman et al 1977
Smithells and Sheppard 1978
Bunde and Bowles 1963
15 (29)
16 (28)
17 (23)
19 (14)
22 (18)
23 (19)
24 (20)
25 (22)
26 (15)
Aselton andJick 1983
18 (13)
–
19,307
240
9,263
31
70
760
184
24
4
366
93
162
Control mal.
–
125,658
607
18,339
1,682
6,671
748
398
57
3,886
1,208
1,222
4,323
Control no mal.
–
174,568
1,020
32,244
3,426
7,933
1,672
603
661
5,254
1,644
1,690
5,196
Total
508
1,116
e
d
11
27
6
76
12
78
52
24
8
Exposedmal.
14,116
22,369
e
d
2,207
1,595
1,186
88
9
1,607
121
46
367
Exposed no mal.
7,402
8,314
e
d
2,197
644
6,671
748
398
5,526
607
1,208
1,285
Control no mal.
10,7082
107,615
e
d
Summary odds ratio
21
8
70
760
184
245
240
366
30
Control mal.
Primary studiesb
12,9108
139,414
e
d
4,436
2,274
7,933
1,672
603
7,456
1,020
1,644
1,690
Total
–
–
–
–
–
–
–
1.07
–
1.04
Antihistamines
0.52
1.36
0.48
0.85
2.88
1.09
1.09
1.72
0.93
(a) Relative riskb (b) Odds ratiob
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Doxylamine
Medication exposure/nonexposureb
–
–
–
–
0.93–1.23
0.91–1.19
0.25–1.08
0.62–3.02
0.21–1.11
0.62–1.17
1.19–6.97
0.84–1.42
0.76–1.55
1.04–2.86
0.42–2.05
95% Confidence intervalb
American Journal of Perinatology
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Abbreviation: mal., malformation. Notes: The numbers presented under the Seto et al meta-analysis heading are stated to represent exposure/nonexposure to antihsitamines.7 The numbers presented under the primary studies heading are raw data abstracted from the original studies. Data are presented for antihistamines and/or doxylamine if such can be abstracted from the original studies. a The numbers in parentheses are reference numbers used in this article. b The data were extracted from primary studies and calculations were performed for the re-analysis in this current study. c The number of unexposed women used in this re-analysis was determined to be 3,891, although both 3,891 and 3,890 were reported in the original primary study. d This reference is a review article and not a primary study. e Duplicate entry of reference 12.
27,142 –
2,461 –
121
3,207
1,685
1,186
88
9
561
1,362
46
344
679
Exposed no mal.
Total (doxylamine)
52
1,435
28
6
76
12
19
2
24
31
32
Exposedmal.
Seto et al meta-analysis7
Total (antihistamines)
(d) Total number of women involved
Ayd 1972
7 (12)
(c) Excluded studies
Author and year
Study reference number in Seto et al meta-analysisa
Table 2 (Continued)
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Table 3 A comparison of Mazzotta and Magee11 and Seto et al7 meta-analyses Seto et al7 Odds ratio (95% CI)
Mazzotta and Magee11 Relative risk (95% CI)
196315
0.90 (0.54–1.51)
0.52 (0.25–1.08)
General Practitioner Research Group
1963
21
0.87 (0.54–1.41)
0.81 (0.19–3.39)
Mellin and Katzenstein
196325
0.99 (0.64–1.53)
Study not of doxylaminea
Nora et al
196738
1.26 (0.20–7.89)
Study not of doxylaminea
Nelson and Forfar
197127
0.52 (0.30–0.92)
Study not of doxylaminea
Kullander and Källén
197616
0.52 (0.25–1.08)
Study not of doxylaminea
1976
26
3.74 (2.98–4.69)
Not included
1977
19
2.88 (1.19–6.97)
0.92 (0.77–1.09)
Heinonen et al
1977
24
0.29 (0.25–0.33)
0.97 (0.77–1.24)
Newman et al
197720
0.85 (0.62–1.17)
0.48 (0.21–1.11)
1978
22
0.48 (0.21–1.11)
1.56 (0.71–3.43)
Rothman et al
1979
28
1.18 (0.78–1.81)
Not included
Michaelis et al
198031
Not included
1.37 (0.86–2.16)
Fleming et al
198139
0.92 (0.64–1.33)
0.81 (0.40–1.62)
1981
14
1.43 (0.26–7.80)
1.09 (0.85–1.40)
Jick et al
1981
17
1.09 (0.84–1.42)
0.87 (0.54–1.40)
Eskenazi and Bracken
198241
1.40 (0.96–2.05)
1.25 (0.98–1.60)
1982
29
1.26 (0.85–1.85)
0.94 (0.43–2.02)
Aselton and Jick
1983
13
1.01 (0.57–1.78)
Not included
Golding et al
198318
0.08 (0.04–0.16)
Not included
1983
40
0.90 (0.56–1.42)
Not included
1985
33
Not included
1.25 (0.82–1.90)
Zierler and Rothman
1985
23
1.72 (1.04–2.86)
Not included
Shiono
198932
Not included
1.02 (0.77–1.36)
Erickson
199134
Not included
0.96 (0.90–1.01)
0.48 (0.04–5.61)
Study not of doxylaminea
0.76 (0.60–0.94)
0.98 (0.93–1.03)
Author
Year
Bunde and Bowles
Milkovich and van den Berg Greenberg et al
Smithells and Sheppard
Gibson et al
Morelock et al
Michaelis et al Aselton et al
Seto et al
1993
37
Pooled
Notes: Relative risks reported in the Mazzotta and Magee’s30 meta-analysis pertain to congenital malformations associated with doxylamine exposure. Odds ratios were not reported for individual studies in the Seto et al meta-analysis.7 Raw data as presented in the table (Seto et al meta-analysis on malformation rates in antihistamine-exposed/unexposed women) were used to calculate odds ratios and 95% CI using RevMan. a “Study not of doxylamine” denotes studies that do not contain specific data on doxylamine exposure.
during the first trimester. In addition, the consumption of other medications was not controlled for and women in either the doxylamine “exposed” or “unexposed” group might have taken other types of medications including medications that are now recognized as teratogens. One of the primary studies used in the Seto et al meta-analysis was a cohort study conducted by Heinonen et al (1977).24 As the largest study with 50,282 participating women, it evaluated many drugs including doxylamine succinate used in the first 4 months of pregnancy and their relations to malformations.
Malformations Examined The definition of malformations was not uniform across studies. Although some studies included both major and American Journal of Perinatology
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minor malformations, other studies excluded malformations considered to be minor by the studies’ researchers such as syndactyly and hypospadias.17
Sample Size, Relative Risk, and Odds Ratio In our current analysis, a total of 139,414 women were involved in 22 of the 24 articles used in the Seto et al metaanalysis (►Table 2). This differs from the reported sample size of “over 200,000 women” in the Seto et al meta-analysis.7 We found that 129,108 of the 139,414 women were in studies involving doxylamine. In all 22 eligible studies, 23,485 women had exposure to antihistamines and 14,624 women had exposure to doxylamine (►Table 2). The summary relative risk for
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707
malformations associated with doxylamine use in the seven cohort studies with applicable doxylamine data was 0.94 (95% CI: 0.80–1.10) (►Table 2a and ►Fig. 1). There was no statistical heterogeneity (I2 ¼ 0). The summary odds ratio was 1.07 (95% CI: 0.93–1.23) in the 10 case–control studies with doxylamine applicable data (►Table 2b and ►Fig. 2). There was moderate heterogeneity (I2 ¼ 55%). The summary relative risk for malformations associated with antihistamine
use was 1.09 (95% CI: 1.01–1.18) in the 11 cohort studies (►Table 2a and ►Fig. 3) with no statistical heterogeneity (I2 ¼ 0), whereas the summary odds ratio was 1.04 (95% CI: 0.91–1.19) in the 11 case–control studies (►Table 2b and ►Fig. 4) with moderate statistical heterogeneity (I2 ¼ 61%). In comparison, the summary odds ratio of major malformations associated with first-trimester antihistamine exposure reported in the Seto et al meta-analysis was lower at
Fig. 2 Summary analysis (odds ratio) for malformations associated with first-trimester doxylamine use in 10 case–control studies. CI, confidence interval; M-H, Mantel-Haenszel.
Fig. 3 Summary analysis (relative risk) for malformations associated with first-trimester antihistamine use in 11 cohort studies. CI, confidence interval; GPRG, General Practitioner Research Group; M-H, Mantel-Haenszel.
American Journal of Perinatology
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Fig. 1 Summary analysis (relative risk) for malformations associated with first-trimester doxylamine use in seven cohort studies.CI, confidence interval; GPRG, General Practitioner Research Group; M-H, Mantel-Haenszel.
Re-analysis of Safety Data Supporting Doxylamine
Chin et al.
Fig. 4 Summary analysis (odds ratio) for malformations associated with first-trimester antihistamine use in 11 case–control studies. CI, confidence interval; M-H, Mantel-Haenszel.
a value of 0.76 (95% CI: 0.60–0.94).7 The relative risk/odds ratio was not reported for each individual study in Table 3 of the Seto et al meta-analysis. Only the summary odds ratio was reported in the text of the article.
Quality of Primary Studies Included in the Seto et al Meta-analysis The primary studies included in the Seto et al meta-analysis with the lowest odds ratios for malformations were the oldest studies and they employed questionable methodologies. In the General Practitioner Clinical Trials, physicians were invited to provide information about patients seen during a prospective 9-month period, but they were also given the option of including patients seen during the previous 6 months.21 The number of patients recruited in each period was not reported, so it is unclear if the retrospective group introduced a selection bias. In the study by Bunde and Bowles (1963), 21 physicians identified to prescribe Bendectin frequently were selected by the Wm. S. Merrell Company (Cincinnati, OH) which manufactured the medication.15 These physicians were asked to complete questionnaires about the use of medications among pregnant patients in their practice. The odds ratio for birth defects associated with Bendectin exposure from this study was 0.52 (95% CI: 0.25– 1.1) which is substantially lower than those found in subsequent studies that employed more conventional methodologies (►Fig. 2).
The More Recent Meta-analysis on Doxylamine Mazzotta and Magee (2000)11 adapted McKeigue et al’s metaanalysis (1994)30 and published another review that included the same 15 primary studies used by McKeigue et al, except one study by Milkovich and van den Berg (1976).26 With a pooled relative risk of 0.98 (95% CI: 0.93–1.03), Mazzotta and Magee concluded that the first-trimester to doxylamine is not associated with an increased risk of major or minor congenital malformations.11 The meta-analyses by Seto et al7 and by Mazzotta and Magee11 included different primary studies (4 of the 16 studies in Mazzotta and Magee’s review were not included in Seto et al’s meta-analysis and 6 of the 22 eligible studies in American Journal of Perinatology
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Seto et al’s meta-analysis were excluded in McKeigue et al’s review30) (►Table 3).
Discussion The Seto et al meta-analysis was performed to examine the safety of antihistamines in general and some of the studies included subsets of data specifically for doxylamine.7 This allowed for the examination of doxylamine’s safety for NVP. The strength of safety data for doxylamine has been overstated. This is important because recommendations for doxylamine are based on the strength of safety data in comparison to other commonly used agents.5 Although our reanalysis and the Seto et al meta-analysis did not identify a strong association between doxylamine use and malformations, doxylamine has not been studied in as many patients as claimed in the Seto et al meta-analysis,7 and our pooled odds ratio for malformations is significantly different (nonoverlapping confidence intervals) from that reported in the Seto et al meta-analysis.7 The Seto et al meta-analysis stated that the “analysis included over 200,000 investigated women in 24 different studies, and therefore it has an unprecedented power to reject the suggestion of teratogenic potential of this class of drugs.”7 Diclectin is recommended as the first-line pharmacological agent for NVP in Canada based on the strength of the safety evidence.5 The Public Health Agency of Canada, referencing the Seto et al meta-analysis only,7 states that “[Diclectin] has been studied in over 200 000 pregnant women and has not been shown to increase the risk of teratogenicity.”4 Our reanalysis identified a total of 139,414 women in reports about the safety of antihistamines and 129,108 in reports about the safety of doxylamine. In these studies, 23,485 women were exposed to antihistamines and 14,624 were exposed to doxylamine. The strength of the safety data for doxylamine relative to other antihistamines is less than previously claimed. Data about other commonly used antihistamines were also provided by some of the primary studies used in the Seto et al meta-analysis7 (►Table 2). For example, the largest cohort study of 50,282 women by Heinonen et al (1977) provides
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Re-analysis of Safety Data Supporting Doxylamine
amine-pyridoxine is associated with an increased risk of malformations the evidence for the safety of doxylamine is not as strong as previously claimed. This current analysis provides a more accurate presentation of the safety data in the primary studies used by Seto et al7 for antihistamines including doxylamine. This should be taken into consideration as recommendations for NVP treatment are revised.
Acknowledgments N.P. is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research and by the Department of Family and Community Medicine, St Michael’s Hospital, Toronto, Canada.
References 1 Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of
2
3
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6
7
8
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11
Conclusion Our current analysis, albeit not a new systematic review, illustrates that the safety of doxylamine use for NVP in the first trimester has been overstated by the Seto et al metaanalysis. As discussed by Matthews et al in their 2010 Cochrane review on the effectiveness and safety on all interventions for NVP, there is currently a lack of consistent outcome measurement and high-quality evidence in the literature.36 As such their review “would not support [the] simplistic conclusion” that “Bendectin/Diclectin, antihistamine blockers, and phenothiazines as a group are safe and effective for treatment” as suggested by others.11 Although doxylamine has been studied in a large number of women and our revised odds ratio does not demonstrate that doxyl-
709
12 13 14
15 16 17
nausea and vomiting during pregnancy. Br J Gen Pract 1993; 43(371):245–248 Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy: a prospective study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol 2000;182(4):931–937 Briggs G, Freeman RK, Yaffe SJ. Doxylamine. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risks. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011:4527 Public Health Agency of Canada. Statement on Pregnancy and Travel; 2010. Available at: http://www.phac-aspc.gc.ca/publicat/ ccdr-rmtc/10vol36/acs-2/index-eng.php. Accessed May 17, 2012 Arsenault MY, Lane CA, MacKinnon CJ, et al. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can 2002; 24(10):817–831, quiz 832–833 Einarson A, Maltepe C, Boskovic R, Koren G. Treatment of nausea and vomiting in pregnancy: an updated algorithm. Can Fam Physician 2007;53(12):2109–2111 Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol 1997;14(3):119–124 Kar S, Krishnan A, Preetha K, Mohankar A. A review of antihistamines used during pregnancy. J Pharmacol Pharmacother 2012; 3(2):105–108 So M, Bozzo P, Inoue M, Einarson A. Safety of antihistamines during pregnancy and lactation. Can Fam Physician 2010;56(5):427–429 Magee LA, Mazzotta P, Koren G. Evidence-based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP). Am J Obstet Gynecol 2002;186(5, Suppl Understanding ):S256–S261 Mazzotta P, Magee LA. A risk-benefit assessment of pharmacological and non-pharmacological treatments for nausea and vomiting of pregnancy. Drugs 2000;59:781–800 Ayd FJ Jr. Haloperidol: fifteen years of clinical experience. Dis Nerv Syst 1972;33(7):459–469 Aselton PJ, Jick H. Additional follow-up of congenital limb disorders in relation to Bendectin use. JAMA 1983;250(1):33–34 Gibson GT, Colley 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(8):410–414 Bunde CA, Bowles DM. A technique for controlled survey of case records. Curr Ther Res Clin Exp 1963;5:245–248 Kullander S, Källén B. A prospective study of drugs and pregnancy. II. Anti-emetic drugs. Acta Obstet Gynecol Scand 1976;55(2):105–111 Jick H, Holmes LB, Hunter JR, Madsen S, Stergachis A. Firsttrimester drug use and congenital disorders. JAMA 1981;246(4): 343–346 American Journal of Perinatology
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safety data for dimenhydrinate and other antihistamines,24 and thus could not be considered a study of doxylamine. There was also a lack of adjustment for confounding factors such as exposure to other potential teratogens in the primary studies. The Seto et al meta-analysis reported an odds ratio of 0.76 (95% CI: 0.60–0.94) for antihistamine use in the first trimester,7 and this is different from our recalculated odds ratio of 1.04 (95% CI: 0.91–1.19). Mazzotta and Magee reported a pooled relative risk of 0.98 (95% CI: 0.93–1.03) and concluded that firsttrimester to doxylamine is not associated with an increased risk of major or minor congenital malformations.11 Mazzotta and Magee did not include the same primary studies in their meta-analysis as Seto et al. The study by Michaelis et al (1980)31 might have been excluded by Seto et al7 as it was published in German. The study by Shiono and Klebanoff (1989)32 did not present an overall “exposed” and “unexposed” rates of outcomes which might have led to its exclusion by Seto et al.7 It is unclear why the two studies by Aselton et al (1985)33 and Erickson (1991)34 were excluded from the Seto et al meta-analysis, 7 as they appeared to meet the inclusion and exclusion criteria set by Seto et al. On the basis of a pooled odds ratio of 0.76 (95% CI: 0.60– 0.94) in the Seto et al meta-analysis, the authors also concluded that antihistamines including doxylamine for NVP may be associated with a protective effect against teratogenic risk.7 Some researchers have taken the pooled odds ratio in the Seto et al meta-analysis and its conclusion7 to indicate that antihistamines including doxylamine may prevent malformations. Fejzo et al (2008) stated that “if treated early, severe nausea may be associated with a protective effect against major malformations” referencing the Seto et al meta-analysis.35 The SOGC guidelines on the management of NVP also cited the Seto et al meta-analysis7 and stated that “data have actually shown a slightly reduced incidence of major and minor malformations with first-trimester exposure to various antihistamines.”5 The more recent meta-analysis by Mazzotta and Magee (2000)11 was not cited for evidence of safety by the SOGC. Our re-analysis together with the meta-analyses by McKeigue et al30 as well as Mazzotta and Magee11 did not show that doxylamine reduces the risk of congenital malformations.
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18 Golding J, Vivian S, Baldwin JA. Maternal anti-nauseants and clefts
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of lip and palate. Hum Toxicol 1983;2(1):63–73 Greenberg G, Inman WHW, Weatherall JAC, Adelstein AM, Haskey JC. Maternal drug histories and congenital abnormalities. BMJ 1977;2(6091):853–856 Newman NM, Correy JF, Dudgeon GI. A survey of congenital abnormalities and drugs in a private practice. Aust N Z J Gynaecol 1977;17:156–159 General Practitioner Research Group. General Practitioner Clinical Trials: DRUGS IN PREGNANCY SURVEY. Practitioner 1963;191:775–780 Smithells RW, Sheppard S. Teratogenicity testing in humans: a method demonstrating safety of bendectin. Teratology 1978; 17(1):31–35 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(6):347–352 Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton MA: PSG Publishing; 1977 Mellin G, Katzenstein M. Meclozine and fetal abnormalities. Lancet 1963;26:222–223 Milkovich L, van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976;125(2): 244–248 Nelson MM, Forfar JO. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. BMJ 1971;1(5748):523–527 Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109(4):433–439 Morelock S, Hingson R, Kayne H, et al. Bendectin and fetal development. A study of Boston City Hospital. Am J Obstet Gynecol 1982;142(2):209–213
defects: I. A meta-analysis of the epidemiologic studies. Teratology 1994;50(1):27–37 Michaelis J, Gluck E, Michaelis H, et al. Does Lenotan have teratogenic effects? Dtsch Arzt 1980;23:1527–1529 Shiono PH, Klebanoff MA. Bendectin and human congenital malformations. Teratology 1989;40(2):151–155 Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. Firsttrimester drug use and congenital disorders. Obstet Gynecol 1985;65(4):451–455 Erickson JD. Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study. Teratology 1991;43(1):41–51 Fejzo MS, Ingles SA, Wilson M, et al. High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals. Eur J Obstet Gynecol Reprod Biol 2008;141(1):13–17 Matthews A, Dowswell T, Haas DM, Doyle M, O’Mathúna DP. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2010(9, Issue 9)CD007575 Seto A, Einarson T, Koren G. Evaluation of brompheniramine safety in pregnancy. Reprod Toxicol 1993;7(4):393–395 Nora JJ, Nora AH, Sommerville RJ, Hill RM, McNamara DG. Maternal exposure to potential teratogens. JAMA 1967;202(12): 1065–1069 Fleming DM, Knox JDE, Crombie DL. Debendox in early pregnancy and fetal malformation. Br Med J (Clin Res Ed) 1981;283(6284):99–101 Michaelis J, Michaelis H, Glück E, Koller S. Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformations. Teratology 1983;27(1):57–64 Eskenazi B, Bracken MB. Bendectin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol 1982;144(8):919–924
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