CORRESPONDENCE
In Utero Exposure to Methotrexate and Risk of Congenital Malformations Per Damkier1* and Yusuf Cem Kaplan2 1
Department of Clinical Chemistry & Pharmacology, Odense University Hospital, Odense, Denmark
2
Terafar-Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey
Manuscript Received: 18 March 2015; Manuscript Accepted: 24 April 2015
To the Editor: We read with interest the article by Dawson et al., [2014] on congenital malformations and maternal exposure to methotrexate (MTX). Unfortunately, we believe that the study and the presentation of results suffer from methodological flaws and inaccuracies. The authors have not discussed their results in the context of other relevant publications to a justifiable extent, and the conclusion by the authors is at least in part unsupported by their data and other available evidence. The authors used data from the National Birth Defects Prevention Study to conduct a case-control study. They identified MTX exposure within 3 months from conception until the end of first trimester among 16 cases and four controls with exposure identified by telephone interviews. While acknowledged by the authors, retrospective exposure remains subject to recall bias and may lead to spurious associations [Rockenbauer et al., 2001]. In this particular case, we believe that the attempt to classify exposure as pre- or post conception by retrospective telephone interview is stretching this approach beyond any validation that we are aware of. Combined with the very few number of exposed cases, the authors should have resisted the futile attempt to discuss various clinical characteristics of these 16 cases and four controls. The methodological issues on exposure validity notwithstanding, no clinically meaningful information can be concluded from such approach. Of the 16 cases with malformations, 11 were cardiovascular and four were reported among preconception only exposure to MTX. The authors find that these observations lend convincing support to a few case reports describing congenital heart defects in mothers exposed to MTX. We disagree. Inferring causality from such observations is only justifiable if the detected malformation is rare and exhibits a repeating pattern. This “astute clinician method”, as suggested by Carey et al., [2009]; cannot be used for assessing possible associations to relatively common malformations such as cardiovascular malformations. The authors do not discuss several papers that do not support the hypothesis that low-dose methotrexate be a clinically important teratogen [Lewden et al., 2004; Svirsky et al., 2009; Martin et al., 2014; Weber-Schoendorfer et al., 2014]. In a prospective study by Weber-Schoendorfer et al. [2014] which included 324 women with low-dose methotrexate exposure from 12-month preconception throughout first trimester, a sta-
© 2015 Wiley Periodicals, Inc.
How to Cite this Article: Damkier P, Kaplan YC. 2015. In utero exposure to methotrexate and risk of congenital malformations. Am J Med Genet Part A 167A:2488–2489.
tistically significant odds ratio of 3.1 (95% CI 1.03–9.5) was detected in the post-conceptional MTX group regarding major congenital malformations compared to women without autoimmune diseases. However, there was no statistically significant increase in risk (OR 1.8, 95% CI 0.6–5.6) for major congenital malformations when post-conceptional MTX group was compared with disease-matched cohort. There were a total of two cardiovascular malformations. No increased risk was observed among 136 preconception only exposures, which is in accordance with other studies [Svirsky et al., 2009; Weber-Schoendorfer et al., 2014]. The latter study was published online on 28 April 2014 and may understandably have eluded the present author group. We are representing two teratology- and drug information services that provide counselling to healthcare professionals on matters of drug exposure during pregnancy and fetal risk. We are having a hard time to see how these findings as presented “..may be helpful to healthcare providers who counsel women prenatally exposed to methotrexate”. On the contrary, we find that such presentations, based on extremely few exposed cases and insufficient discussions of findings in a proper perspective to other available data, only serve to confuse healthcare decision-makers and patients.
Conflict of interest: None. Correspondence to: Per Damkier, Department of Clinical Chemistry & Pharmacology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense, Denmark E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 May 2015 DOI 10.1002/ajmg.a.37153
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REFERENCES Carey JC, Martinez L, Balken E, Leen-Mitchell M, Robertson J. 2009. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res A Clin Mol Teratol 85:63–68. Dawson AL, Riehle-Colarusso T, Reefhuis J, Arena JF. 2014. National Birth Defects Prevention Study. Maternal exposure to methotrexate and birth defects: A population-based study. Am J Med Genet Part A 164A:2212–2216. Lewden B, Vial T, Elefant E, Nelva A, Carlier P, Descotes J. 2004. French Network of Regional Pharmacovigilance Centers. Low dose methotrexate in the first trimester of pregnancy: Results of a French collaborative study. J Rheumatol 31:2360–2365. Koren G. 2014. Martı´n MC, Barbero P, Groisman B, Aguirre MA, Methotrexate embryopathy after exposure to low weekly doses in early pregnancy. Reprod Toxicol 43:26–29.
2489 Rockenbauer M, Olsen J, Czeizel AE, Pedersen L. 2001. Sørensen HT; EuroMAP Group. Recall bias in a case-control surveillance system on the use of medicine during pregnancy. Epidemiology 12:461–466. Svirsky R, Rozovski U, Vaknin Z, Pansky M, Schneider D, Halperin R. 2009. The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 27:85–87. Weber-Schoendorfer C, Chambers C, Wacker E, Beghin D, Bernard N, Network of FrenchPharmacovigilance Centers, Shechtman S, Johnson D, Cuppers-Maarschalkerweerd B, Pistelli A, Clementi M, Winterfeld U, Eleftheriou G, Pupco A, Kao K, Malm H, Elefant E, Koren G, Vial T, Ornoy A, Meister R, Schaefer C. 2014. Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: A prospective multicenter cohort study. Arthritis Rheumatol 66:1101–1110.
In Utero Exposure to Methotrexate and Risk of Congenital Malformations Per Damkier1* and Yusuf Cem Kaplan2 1
Department of Clinical Chemistry & Pharmacology, Odense University Hospital, Odense, Denmark
2
Terafar-Izmir Katip Celebi University Teratology Information, Training and Research Center, Izmir, Turkey
Manuscript Received: 18 March 2015; Manuscript Accepted: 24 April 2015
To the Editor: We read with interest the article by Dawson et al., [2014] on congenital malformations and maternal exposure to methotrexate (MTX). Unfortunately, we believe that the study and the presentation of results suffer from methodological flaws and inaccuracies. The authors have not discussed their results in the context of other relevant publications to a justifiable extent, and the conclusion by the authors is at least in part unsupported by their data and other available evidence. The authors used data from the National Birth Defects Prevention Study to conduct a case-control study. They identified MTX exposure within 3 months from conception until the end of first trimester among 16 cases and four controls with exposure identified by telephone interviews. While acknowledged by the authors, retrospective exposure remains subject to recall bias and may lead to spurious associations [Rockenbauer et al., 2001]. In this particular case, we believe that the attempt to classify exposure as pre- or post conception by retrospective telephone interview is stretching this approach beyond any validation that we are aware of. Combined with the very few number of exposed cases, the authors should have resisted the futile attempt to discuss various clinical characteristics of these 16 cases and four controls. The methodological issues on exposure validity notwithstanding, no clinically meaningful information can be concluded from such approach. Of the 16 cases with malformations, 11 were cardiovascular and four were reported among preconception only exposure to MTX. The authors find that these observations lend convincing support to a few case reports describing congenital heart defects in mothers exposed to MTX. We disagree. Inferring causality from such observations is only justifiable if the detected malformation is rare and exhibits a repeating pattern. This “astute clinician method”, as suggested by Carey et al., [2009]; cannot be used for assessing possible associations to relatively common malformations such as cardiovascular malformations. The authors do not discuss several papers that do not support the hypothesis that low-dose methotrexate be a clinically important teratogen [Lewden et al., 2004; Svirsky et al., 2009; Martin et al., 2014; Weber-Schoendorfer et al., 2014]. In a prospective study by Weber-Schoendorfer et al. [2014] which included 324 women with low-dose methotrexate exposure from 12-month preconception throughout first trimester, a sta-
© 2015 Wiley Periodicals, Inc.
How to Cite this Article: Damkier P, Kaplan YC. 2015. In utero exposure to methotrexate and risk of congenital malformations. Am J Med Genet Part A 167A:2488–2489.
tistically significant odds ratio of 3.1 (95% CI 1.03–9.5) was detected in the post-conceptional MTX group regarding major congenital malformations compared to women without autoimmune diseases. However, there was no statistically significant increase in risk (OR 1.8, 95% CI 0.6–5.6) for major congenital malformations when post-conceptional MTX group was compared with disease-matched cohort. There were a total of two cardiovascular malformations. No increased risk was observed among 136 preconception only exposures, which is in accordance with other studies [Svirsky et al., 2009; Weber-Schoendorfer et al., 2014]. The latter study was published online on 28 April 2014 and may understandably have eluded the present author group. We are representing two teratology- and drug information services that provide counselling to healthcare professionals on matters of drug exposure during pregnancy and fetal risk. We are having a hard time to see how these findings as presented “..may be helpful to healthcare providers who counsel women prenatally exposed to methotrexate”. On the contrary, we find that such presentations, based on extremely few exposed cases and insufficient discussions of findings in a proper perspective to other available data, only serve to confuse healthcare decision-makers and patients.
Conflict of interest: None. Correspondence to: Per Damkier, Department of Clinical Chemistry & Pharmacology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense, Denmark E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 May 2015 DOI 10.1002/ajmg.a.37153
2488
DAMKIER AND KAPLAN
REFERENCES Carey JC, Martinez L, Balken E, Leen-Mitchell M, Robertson J. 2009. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res A Clin Mol Teratol 85:63–68. Dawson AL, Riehle-Colarusso T, Reefhuis J, Arena JF. 2014. National Birth Defects Prevention Study. Maternal exposure to methotrexate and birth defects: A population-based study. Am J Med Genet Part A 164A:2212–2216. Lewden B, Vial T, Elefant E, Nelva A, Carlier P, Descotes J. 2004. French Network of Regional Pharmacovigilance Centers. Low dose methotrexate in the first trimester of pregnancy: Results of a French collaborative study. J Rheumatol 31:2360–2365. Koren G. 2014. Martı´n MC, Barbero P, Groisman B, Aguirre MA, Methotrexate embryopathy after exposure to low weekly doses in early pregnancy. Reprod Toxicol 43:26–29.
2489 Rockenbauer M, Olsen J, Czeizel AE, Pedersen L. 2001. Sørensen HT; EuroMAP Group. Recall bias in a case-control surveillance system on the use of medicine during pregnancy. Epidemiology 12:461–466. Svirsky R, Rozovski U, Vaknin Z, Pansky M, Schneider D, Halperin R. 2009. The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 27:85–87. Weber-Schoendorfer C, Chambers C, Wacker E, Beghin D, Bernard N, Network of FrenchPharmacovigilance Centers, Shechtman S, Johnson D, Cuppers-Maarschalkerweerd B, Pistelli A, Clementi M, Winterfeld U, Eleftheriou G, Pupco A, Kao K, Malm H, Elefant E, Koren G, Vial T, Ornoy A, Meister R, Schaefer C. 2014. Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: A prospective multicenter cohort study. Arthritis Rheumatol 66:1101–1110.
