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Research

Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion

Hamid Reza Nakhai-Pour, Perrine Broy, Odile Sheehy and Anick Bérard
CMAJ October 18, 2011 183 (15) 1713-1720; DOI: https://doi.org/10.1503/cmaj.110454
Hamid Reza Nakhai-Pour
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Perrine Broy
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Odile Sheehy
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Anick Bérard
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  • For correspondence: anick.berard@umontreal.ca
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  • Use of nonaspirin NSAID drugs during pregnancy and the risk of spontaneous abortion.
    Soon-Cheol Hong
    Posted on: 31 October 2011
  • Re:Re: Use of non-aspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion
    Anick Berard
    Posted on: 03 October 2011
  • Ibuprofen
    Hali Sokolowski
    Posted on: 03 October 2011
  • Re: Use of non-aspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion
    Christine A. Clark
    Posted on: 22 September 2011
  • Posted on: (31 October 2011)
    Use of nonaspirin NSAID drugs during pregnancy and the risk of spontaneous abortion.
    • Soon-Cheol Hong, Associate professor
    • Other Contributors:

    Dear editor: We found the study by Nakhai-Pour et al. entitled "Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion" very interesting. However, we would like to clarify a number of points made in the paper. First of all, I noticed that the control group showed high exposure rate to antiemetic agents(cases 3.4%, controls 15.2% p<0.0001). It is well- known that n...

    Show More

    Dear editor: We found the study by Nakhai-Pour et al. entitled "Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion" very interesting. However, we would like to clarify a number of points made in the paper. First of all, I noticed that the control group showed high exposure rate to antiemetic agents(cases 3.4%, controls 15.2% p<0.0001). It is well- known that nausea and vomiting are associated with a decreased risk of miscarriage.2 I don't think we could interpret it as that antiemetic agents may decrease the risk of spontaneous abortion. Similarly, in considering the cause of abortion, the chromosomal anomalies cause at least half of early spontaneous abortion. The other risk factors are maternal age, parity, smoking, infection and chronic disease, etc. 3 But there seemed to be no data about parity, smoking, infection or underlying inflammatory condition. The increased use of nonaspirin NSAID could be the consequence of underlying inflammatory disease associated with abortion instead of a cause for the increased abortion. Such underlying inflammatory condition including infection could be the cause, and therefore should be considered along with parity and smoking. I suggest that the author consider including such confounding factors in the paper. Second, the author explained the mechanism as a defect in suppression of prostaglandins throughout gestation. Because the main mechanism of NSAID is the decrease in the synthesis of prostaglandin, this is an inadequate explanation. Last point involves the correction of a minor terminology in the paper. In the third page(page 1715), author described "who had spontaneous abortion after 20 weeks' gestation." The WHO (World Health Organization) defined abortion as pregnancy termination prior to 20 weeks' gestation. The adequate terminology after 20 weeks' gestation is preterm birth. Thank you.

    Reference 1. Nakhai-Pour HR, Broy P, Sheehy O, Berard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 2011; 183(15): 1713-20 2. Weigh MM, Weigel RM. Nausea and vomiting of early pregnancy and pregnancy outcomes: an epidemiological study. Br J Obstet Gynaecol 1989; 96: 1304-11 3. Cunningham. Williams Obstetrics 23rd edition. McGraw-Hill 2010; page 215-218

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Posted on: (3 October 2011)
    Re:Re: Use of non-aspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion
    • Anick Berard, Full Professor
    • Other Contributors:

    Dear Editor,

    We would like to thank Dr Clark and colleagues for their letter on our paper published in CMAJ (1), and we thank CMAJ for giving us the opportunity to answer. We disagree with the majority of what Clark et al. have put forward but we agree that prescription medications do not necessarily indicate that women take their medications as was mentioned in our discussion section. However, our study defined...

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    Dear Editor,

    We would like to thank Dr Clark and colleagues for their letter on our paper published in CMAJ (1), and we thank CMAJ for giving us the opportunity to answer. We disagree with the majority of what Clark et al. have put forward but we agree that prescription medications do not necessarily indicate that women take their medications as was mentioned in our discussion section. However, our study defined NSAIDs exposure dichotomously and thus anyone taking at least one pill was defined as being exposed. Given that NSAIDs use is on an acute basis even when used for chronic conditions such as rheumatoid arthritis or lupus, it is very unlikely that women who took the time to go to the pharmacy and gave out of pocket money did not take at least one pill. Furthermore, Glover et al. (2) have shown that the majority of pregnant women who fill a prescription take it, and Daniels et al. (3) have shown that self-reporting measures of medication use does not provide accurate measurements of adherence when compared with electronic monitoring as was the case in our study.

    Our study team has performed and is still performing many validation studies within the Quebec Pregnancy Registry (which includes data from the RAMQ, MED-ECHO, ISQ and a maternal self-administered questionnaire) to increase internal and external validity. Unlike what Clark and colleagues put forward, we feel it is important to do these studies to help us assess potential biases that might arise from our studies. This is why we are referring to these studies in our paper just published in CMAJ. The fact that Clark et al. have referenced a study performed by our team to assess generalizability of study findings and put it in the context of interval validity shows a clear misunderstanding of perinatal pharmacoepidemiology.

    Data on maternal smoking and BMI is only available on a subset of women (n=3273) included in the Quebec Pregnancy Registry. This was acknowledged in our discussion section. It remains however that for these variables to bias our results, they need to confound the effect. Hence, for smoking and BMI to be confounders, they need to be associated with both the outcome (spontaneous abortion), and independently and separately the exposure (NSAIDs). Hence, Delaney et al. (4) have shown that smoking and BMI were not associated with prescribed NSAIDs use or over-the-counter (OTC) NSAIDs use. Our discussion clearly states that. With this information at hand, although data on smoking and BMI were missing from our analyses, it is very unlikely that this would have biased our estimates.

    Clark et al. are suggesting that we should compare the obstetrical histories and pre-existing comorbidities of the subgroup of women who filled a prescription for NSAIDs and had a spontaneous abortions, and the group that filled a prescription NSAIDs and did not have a spontaneous abortion. Assuming that they would also like us to adjust for time of follow-up during pregnancy, which is essential to correctly answer their question, we would end up with the results we are presenting in our paper. Indeed, this is exactly what we have done. We have shown that there were differences in health care utilization and comorbidities between cases and controls, and NSAID users and non-users. These differences were adjusted for in our multivariate analyses.

    Clark et al. are suggesting that OTC NSAID use was not considered in our study, and this seriously flawed our results. As was mentioned in our paper, prescribed OTC NSAIDs were considered. Indeed, the Registry includes data on prescription medication use (OTC included) during gestation and no data are available on OTC medication use without a prescription. In the case of NSAIDs, the only NSAID available OTC in Canada is ibuprofen. As highlighted in our CMAJ paper, although our study looked at OTC ibuprofen obtained with a prescription, it is true that the number of women who used ibuprofen OTC without a prescription could not be measured. However, there is no reason to believe that women who miscarried used more or less ibuprofen OTC without a prescription than those who did not miscarry as was wrongly insinuated, leading to non-differential misclassification. Hence, even if OTC ibuprofen use without a prescription was not measured in the study, the study estimate is an underestimate of the true effect, meaning that if we had had data on OTC NSAID medication use without a prescription, the estimate would have been higher. This was explained in our manuscript. Interpreting results differently is a misunderstanding of the results.

    The aim of our study, or any other studies performed in pregnant women, is not to scare women but to better inform women and physicians on the potential risks of medication use during pregnancy. This is even more important given that 50% of women do not plan their pregnancy (where the majority of inadvertent exposures occur). We strongly believe that more data (as opposed to withholding of data) are needed regarding medication use during pregnancy, and that pregnancy does not make women unable to make appropriate decision regarding their health during this critical period. Good quality data on large cohorts of pregnant women empower women and do not scare them.

    Anick Berard PhD and Odile Sheehy MSc University of Montreal and CHU Ste-Justine

    References

    1. Nakhai-Pour HR, Broy P, Sheehy O, Berard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ. 2011 Sep 6. [Epub ahead of print] 2. Glover DD, Amonkar M, Rybeck BF, Tracy TS. Prescription, over-the- counter, and herbal medicine use in a rural, obstetric population. Am J Obstet and Gynecol 2003 ;188 :1039-1045. 3. Daniels T, Goodacre L, Sutton C, Pollard K, Conway S, Peckham D. Accurate assessment of adherence: self-report and clinician report vs electronic monitoring of nebulizers. Chest 2011 ;140:425-432. 4. Delaney JA, Biggs ML, Kronmal RA, Psaty BM. Demographic, medical, and

    behavioral characteristics associated with over the counter non- steroidal

    anti-inflammatory drug use in a population-based cohort: results from the Multi-Ethnic Study of Atherosclerosis. Pharmacoepidemiol Drug Saf 2011 ;20:83-89.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Posted on: (3 October 2011)
    Ibuprofen
    • Hali Sokolowski, interested reader

    This is a very interesting result from a study of miscarriages. I am not in the medical field, but I think a lot, i am very science oriented. I just had a thought about a link between Autism and Ibuprofen. Everyone in the U.S. tries to blame our milk or vaccines on the increase of Autism, but has anyone thought of Ibuprofen, it has gained popularity in the last 20-25 years and so has Autism.

    Thank you for lett...

    Show More

    This is a very interesting result from a study of miscarriages. I am not in the medical field, but I think a lot, i am very science oriented. I just had a thought about a link between Autism and Ibuprofen. Everyone in the U.S. tries to blame our milk or vaccines on the increase of Autism, but has anyone thought of Ibuprofen, it has gained popularity in the last 20-25 years and so has Autism.

    Thank you for letting me share my idea.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Posted on: (22 September 2011)
    Re: Use of non-aspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion
    • Christine A. Clark, Research Associate
    • Other Contributors:

    Dear Sir

    We read with interest Nakhai-Pour et al 's paper(1) reporting a possible increase of risk of spontaneous abortion associated with any type or dose of non-aspirin nonsteroidal anti-inflammatory drug (NSAID). This finding supports earlier work by Nielsen et al (2) but as both used a combination of population-based prescription drug registries and pregnancy outcome databases, this similar finding is not su...

    Show More

    Dear Sir

    We read with interest Nakhai-Pour et al 's paper(1) reporting a possible increase of risk of spontaneous abortion associated with any type or dose of non-aspirin nonsteroidal anti-inflammatory drug (NSAID). This finding supports earlier work by Nielsen et al (2) but as both used a combination of population-based prescription drug registries and pregnancy outcome databases, this similar finding is not surprising. It does, however, indicate that the same criticism directed at the earlier study's design(3) can also be made for this latest study, specifically that filling a prescription does not adequately represent actually using the drug, thereby rendering the findings unreliable. Nakhai-Pour et al do provide a reference supporting the validation of risk assessment studies using the prescription drug database (RAMQ) for pregnant women, but the citation is from their own institution and includes one of their co- authors, thus raising the possibility that the validation might be lacking the necessary degree of independence or objectivity(4). Indeed, that paper concluded that the "substantial differences between pregnant women insured by the RAMQ-Rx and those insured by private drug insurance plans" would "most likely limit generalizability" of studies using the RAMQ database"(4).

    Nakhai et al stated that "to their knowledge", neither smoking nor body mass index (BMI) are risk factors for spontaneous abortion and therefore neither needed to be considered as a confounding factor for their analyses. They cite their own earlier work as the source for this statement(5). We performed a simple Pubmed search and found that not only maternal, but also paternal and environmental exposure to smoking are all reported to be associated with increased incidence of spontaneous miscarriage(6-8). In addition, a recent meta-analysis of the risk of BMI on spontaneous abortion revealed that patients with a BMI > 25 kg/m2 have significantly higher odds of miscarriage regardless of method of conception(9), and evidence-based guidelines for the investigation and treatment of recurrent miscarriage include BMI as a risk factor(10). We are aware that Nakhai-Pour et al were not able to ascertain the smoking and BMI status of their cohorts because of their study design, but suggest that the absence of consideration of these factors puts their findings further in doubt.

    We feel it would be interesting if the authors compared the obstetric histories and pre-existing comorbidities of the subgroup of women who filled prescriptions for nonaspirin NSAID and had a live birth (n = 1213) with the subgroup that filled the same prescriptions but had a spontaneous abortion (n = 352). This might reveal a distinct demographic at increased risk of miscarriage.

    Because this was a population-based study, the authors were unable to assess over-the-counter (OTC) NSAID usage. In 2005, Werler et al reported that OTC medication use is extremely common during pregnancy(11). While it may be an epidemiologic truism that an association between a common occurrence and a rare marker cannot be demonstrated, it should be possible to find an association, if one exists, between two common events, notably NSAID usage and spontaneous abortion. It is apparent, therefore, that a study is required that includes both OTC and prescription NSAID use during pregnancy and that analyses must control for all understood confounding factors for each event. Until then, we are left with papers like this that provide subsets of data that suggest an association, but which do not adequately support their claims.

    References 1. Nakhai-Pour HR, Broy P, Sheehy O, Berard A. Use of nonaspirin anti- inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ Epub September 6, 2011. 2. Nielsen GH, S?rensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti- inflammatory drugs: population-based observational study and case-control study. BMJ 2001;322:266-70. 3. Chan LY, Yuen PM. Risk of miscarriage in pregnant users of NSAIDs: more information is needed to be able to interpret study's results [Letter]. BMJ 201;322:1365. 4. Berard A, Lacasse A. Validity of perinatal pharmacoepidemiologic studies using data from the RAMQ administrative database. Can J Clin Pharmacol 2009;16:e360-9. 5. Nakhai-Pour HR, Broy P, Berard A. Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ 2010;182:1031-7. 6. Russell CS, Taylor R, Law CE. Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weight and growth and other related factors. Brit J Prev Soc Med 1968;22:119-26. 7. George L, Granath F, Johansson AL, Anneren G, Cnattingius S. Environmental tobacco smoke and risk of spontaneous abortion. Epidemiology 2006;17:500-5. 8. Blanco-Munoz J, Torres-Sanchez L, Lopez-Carrillo L. Exposure to maternal and paternal tobacco consumption and risk of spontaneous abortion. PHR 2009;124:317-22. 9. Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril 2008;90:714-26. 10. Jauniaux E. Farquharson RG, Christiansen OB, Exalto N.Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 2006;21:2216-22. 11. Werler MM, Mitchell AA, Hernandez-Diaz S, Honein MA, and the National Birth Defects Prevention Study. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol 2005;193:771-7.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
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Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion
Hamid Reza Nakhai-Pour, Perrine Broy, Odile Sheehy, Anick Bérard
CMAJ Oct 2011, 183 (15) 1713-1720; DOI: 10.1503/cmaj.110454

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Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion
Hamid Reza Nakhai-Pour, Perrine Broy, Odile Sheehy, Anick Bérard
CMAJ Oct 2011, 183 (15) 1713-1720; DOI: 10.1503/cmaj.110454
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