www.AJOG.
org
participation and may be subject to recall bias. Time between birth
and study participation may account for the low reported use of as-
pirin and NSAIDs compared with the report of Tyler et al.1 Our anal-
ysis adjusts for similar, but not identical, confounders. It is possible
that NSAID and aspirin use is higher among mothers who deliver
very preterm infants when compared with mothers who deliver at
term. The results reported by Tyler et al1 for infants who are born at
⬍28 weeks’ gestation may not generalize to children with cerebral
palsy who are born at later gestational ages.
Thequestionofover-the-countermedicationsandcerebralpalsyis
difficult to answer because prospective studies with high-quality data
provide small samples; however, larger cohorts from retrospective
studies provide less reliable data. f 3. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral
Michael E. O’Callaghan, PhD
Alastair H. MacLennan, MD
Discipline of Obstetrics and Gynaecology
The use of aspirin during pregnancy
TO THE EDITORS: It is with interest but not without surprise that
we read the case-control study of Tyler et al,1 which attempted to
evaluate the association between antiinflammatory drugs and cere-
bral palsy in very preterm neonates. Beyond the fact that the authors’
conclusions are not in agreement with the highest level of evidence
and do not acknowledge the numerous limitations, they have the
potential to mislead both women and health care providers by sug-
gesting that aspirin may cause brain damage, thereby compromising
the appropriate use of an inexpensive and widely available treatment
that can prevent serious maternal and neonatal morbidities.
Randomized controlled trials and metaanalysis—the highest
levels of evidence available— have demonstrated that low-dose
aspirin initiated before 16 weeks’ gestation is associated with a
significant decrease of preeclampsia and intrauterine growth
restriction, and most likely the severe and preterm forms of
these diseases.2,3 It remains unclear whether low-dose aspirin
prevents the placenta-mediated disease or delay its onset by
improving impaired placentation. Nevertheless, as observed by
Tyler et al1 and in agreement with current best evidence, aspirin
leads to a decrease of early-onset preeclampsia and therefore a
decrease in the rate of very preterm births related to preeclampsia.
High-risk women who delivered before 28 weeks despite the ap-
propriate use of aspirin were potentially destined to worse perina-
tal outcomes without the use of aspirin. Moreover, initiation of
aspirin in women with preterm labor or premature rupture of
membrane could have led to the prolongation of pregnancy and
the further growing of intraamniotic infection and inflammation:
a major contributor to cerebral palsy. The current study design
does not allow for adjustment for such potential selection biases.
Data concerning the dosage and timing of aspirins’ use could
have definitively affected the results of the study. Aspirin initi-
ated when deep placentation disorders are irreversible, is not
beneficial, and in fact potentially harmful. An increased risk of
placenta abruption cannot be excluded when low-dose aspirin
Letters to Editors
School of Paediatrics and Reproductive Health
Robinson Institute
The University of Adelaide, Australia
michael.ocallaghan@adelaide.edu.au
The authors report no conflict of interest.
REFERENCES
1. Tyler CP, Paneth N, Allred EN, et al. Brain damage in preterm newborns and
maternal medication: the Elgan study. Am J Obstet Gynecol 2012;207:
192.e1-9.
2. O’Callaghan ME, MacLennan AH, Gibson CS, et al. The Australian
Cerebral Palsy Research study: protocol for a national collaborative study
investigating genomic and clinical associations with cerebral palsy. J Pae-
diatr Child Health 2011;47:99-110.
palsy: a meta-analysis. JAMA 2000;284:1417-24.
© 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.
2012.11.022
is begun after 16 weeks (relative risk, 1.56; 95% confidence
interval, 0.96 –2.55).2,4
Finally, it is submitted that in accordance with the highest
level of evidence, the only conclusions that can validly be de-
rived from the Tyler et al1 study are as follows: (1) random use
of aspirin during pregnancy may be harmful; (2) aspirin should
not be used when intraamniotic infection is suspected; and (3)
low-dose aspirin should be reserved for accurately identified
women at high-risk for placenta mediated complications and
initiated in early gestation. f
Suzanne Demers, MD
Stéphanie Roberge, MSc
Emmanuel Bujold, MD, MSc, FRCSC
Department of Obstetrics and Gynecology
Faculty of Medicine
Université Laval
Centre de recherche du Centre Hospitalier Universitaire de Québec
(CRCHUQ)
2705 Laurier Blvd.
Québec, QC
Canada G1V 4G2
emmanuel.bujold@crchul.ulaval.ca
All the authors meet requirement for authorship and agreed with the final
version. The authors report no financial or other conflict of interest.
Dr Emmanuel Bujold holds a Clinician Scientist Award from the Canadian
Institute for Health Research and the Jeanne et Jean-Louis Lévesque
Research Chair at Université Laval.
REFERENCES
1. Tyler CP, Paneth N, Allred EN, et al. Brain damage in preterm newborns
and maternal medication: the ELGAN Study. Am J Obstet Gynecol
2012;207:192.e1-9.
2. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and
intrauterine growth restriction with aspirin started in early pregnancy: a
meta-analysis. Obstet Gynecol 2010;116:402-14.
FEBRUARY 2013 American Journal of Obstetrics & Gynecology 161
Letters to the Editors
3. Roberge S, Villa P, Nicolaides K, et al. Early administration of low-dose
aspirin for the prevention of preterm and term preeclampsia: a systematic
review and meta-analysis. Fetal Diagn Ther 2012;31:141-6.
4. Sibai BM, Caritis SN, Thom E, et al. Prevention of preeclampsia with
low-dose aspirin in healthy, nulliparous pregnant women. The National
Institute of Child Health and Human Development Network of Maternal-
Fetal Medicine Units. N Engl J Med 1993;329:1213-8.
© 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.
2012.11.024
REPLY
We thank Drs O’Callaghan and MacLennan and their cowork-
ers for their interest in our article.
We appreciate that Drs O’Callaghan and MacLennan at-
tempted to replicate our findings. Differing results may be due
to the fact that their sample includes infants of all gestational
ages and does not provide separate analyses for the subsample
of infants who were born at ⬍28 weeks of gestation.
We also thank Drs Demmers and Bujold and Ms Roberge
for their interest in our article and regret that they were not
pleased with our findings and conclusions. They suggested
that we could “mislead both women and healthcare provid-
ers. . .thereby compromising the appropriate use of a treat-
ment that can prevent serious maternal and neonatal mor-
bidities.” However, our study did not examine the effect of
low-dose aspirin and the subsequent risk of preeclampsia or
intrauterine growth restriction. In our study, only 2% of
pregnant women with severe preeclampsia reported aspirin
consumption; we have no knowledge of the women who
took aspirin and did not deliver at ⬍28 weeks of gestation.
Thus, our findings cannot speak to the efficacy of low-dose
468
162 American Journal of Obstetrics & Gynecology FEBRUARY 2013
www.AJOG.org
aspirin in the prevention of severe preeclampsia and there-
fore should not be viewed as calling into question reports of
the benefits of aspirin prophylaxis.
We agree with their comment that women who deliver at
⬍28 weeks of gestation generally have the worst perinatal out-
comes; however, our entire sample fell into this category, and,
as such, this would not have biased our conclusions. We also
agree that not having information about the dosage and timing
of medication use is a limitation of our study; we mentioned
this point in the limitations section of our article: “. . .perhaps
equally important is our not having assessed the timing, indi-
cation, or dosage of over-the-counter medications.”
We stand by our conclusion that “the possibility that aspirin
and NSAID [nonsteroidal antiinflammatory drug] use in preg-
nancy could lead to perinatal brain damage cannot be ex-
cluded” and wrote our article to point out what might be a
hazard. However, the last sentence of our article emphasizes
our recognition that our findings might reflect random phe-
nomena; “since we are the first to our knowledge to identify
this association, we encourage others to confirm or refute our
findings.” f
Crystal P. Tyler, for the ELGAN Study Authors
CDC
Division of Reproductive Health
4770 Buford Highway MS K-22
Atlanta, GA 30341
ctyler@cdc.gov
The authors report no conflict of interest.
© 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.
2012.11.023