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N onaspirin nonsteroidal anti-infammatory drugs (NSAIDs) are oneo the most commonly used medicationsduring pregnancy (17%).1 Nevertheless, gesta-tional use o nonaspirin NSAIDs remains contro-versial, partly due to the inconsistency o resultsrom studies on their potential risks, the potentialor residual conounding by comorbidities and

the lack o data on the risks associated with spe-cic types and dosages.15 The strongest associa-tion thus ar was seen when nonaspirin NSAIDshad been used close to the time o conception,suggesting bias that could be partly explained bywomen using the drug to alleviate cramping, aprecursor to spontaneous abortion.4 No one hasdocumented the risk o spontaneous abortionaccording to type and dosage o nonaspirinNSAIDs both important elements to considerwhen determining causality.

We perormed a nested casecontrol study toquantiy the risk o spontaneous abortion associ-ated with specic types and dosages o non-aspirin NSAIDs in a cohort o pregnant women,adjusting or potential conounders.

Methods

Study designWe used a nested casecontrol study design. Wechose this design because it shows similar eectsizes to a prospective cohort approach with time-varying exposure to medication, but with greatercomputational eciency.6

Data collectionWe used data rom the Quebec Pregnancy Reg-istry, an ongoing registry o all pregnancies inQuebec since 1997. Records in the registry are

Use o nonaspirin nonsteroidal anti-infammatory drugsduring pregnancy and the risk o spontaneous abortion

Hamid Reza Nakhai-Pour MD PhD, Perrine Broy BSc, Odile Sheehy MSc, Anick Brard PhD

Competing interests: Nonedeclared.

This article has been peerreviewed.

Correspondence to:Dr. Anick Brard,anick.berard@umontreal.ca

CMAJ2011. DOI:10.1503/cmaj.110454

ResearchCMAJ

Background: The association between the useo nonaspirin nonsteroidal anti-infammatorydrugs (NSAIDs) during pregnancy and the risko spontaneous abortion remains unclearbecause o inconsistent research results andthe lack o evidence or an eect due to spe-cic types or dosages o nonaspirin NSAIDs.

We aimed to quantiy the associationbetween having a spontaneous abortion andtypes and dosages o nonaspirin NSAIDs in acohort o pregnant women.

Methods: Using a nested casecontrol design,we obtained data rom the Quebec Preg-nancy Registry or 4705 women who had aspontaneous abortion. For each instance, werandomly selected 10 controls rom theremaining women in the registry who werematched by index date (date o the sponta-neous abortion) and gestational age. Use ononaspirin NSAIDs (identied by lled pre-scriptions) and nonuse were compared. Wealso looked or associations between dier-ent types and dosages o nonaspirin NSAIDsand having a spontaneous abortion. Analyses

o associations and adjustment or conound-ing were done using conditional logisticregression.

Results: We identied 4705 cases o sponta-neous abortion (352 exposed [7.5%]); 47 050controls (1213 exposed [2.6%]). Adjusting or

potential conounders, the use o nonaspirinNSAIDs during pregnancy was signicantlyassociated with the risk o spontaneous abor-tion (odds ratio [OR] 2.43, 95% condenceinterval [CI] 2.122.79). Specically, use odicloenac (OR 3.09, 95% CI 1.964.87),naproxen (OR 2.64, 95% CI 2.133.28), celecoxib(OR 2.21, 95% CI 1.423.45), ibuproen (OR2.19, 95% CI 1.612.96) and roecoxib (OR 1.83,95% CI 1.242.70) alone, and combinationsthereo (OR 2.64, 95% CI 1.594.39), were allassociated with increased risk o spontaneousabortion. No doseresponse eect was seen.

Interpretation: Gestational exposure to anytype or dosage o nonaspirin NSAIDs mayincrease the risk o spontaneous abortion.These drugs should be used with caution dur-ing pregnancy

Abstract

2011 Canadian Medical Association or its licensors CMAJ 1

Early release, published at www.cmaj.ca on September 6, 2011. Subject to revision.

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linked to those in three administrative databases:the Rgie de lassurance maladie du Qubec(RAMQ) database, Med-cho and the Institut dela statistique du Qubec.

The RAMQ database contains prospectivelycollected inormation on medical services, lledprescriptions, physician-based diagnoses (ac-cording to the International Classifcation o

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Table 1: Characteristics of cases and controls

No. (%)*

CharacteristicCases

(n = 4 705)Controls

(n = 47 050) p value

Age on gestation day 1, yr, mean (SD) 28.7 (6.6) 27.4 (5.6) < 0.0001

Gestational age at index date, w, mean (SD) 10.5 (4.2) 10.5 (5.6) 0.99

Urban residence 3 676 (78.1) 36 208 (77.0) 0.07

Receiving social assistance 1 618 (34.4) 14 044 (29.8) < 0.0001

Use of medication from start of pregnancy to index date

Use of NSAIDs 352 (7.5) 1 213 (2.6) < 0.0001

Use of other medications 1.00

Antidepressant agents 227 (4.8) 1 159 (2.5) < 0.0001

Systemic anti-infective agents 721 (15.3) 6 544 (13.9) 0.008

Oral corticosteroids 60 (1.3) 283 (0.6) < 0.0001

Antiemetic agents 162 (3.4) 7 151 (15.2) < 0.0001

Other 1 937 (41.2) 13 544 (28.8) < 0.0001

Prenatal visits, no.

02 4 231 (89.9) 28 587 (60.8) 1.00

3 474 (10.1) 18 463 (39.2) < 0.001

Comorbidities during year before pregnancy

Diabetes mellitus 77 (1.6) 459 (1.0) < 0.0001

Cardiovascular disease 81 (1.7) 667 (1.4) 0.10

Asthma 932 (19.8) 8 099 (17.2) < 0.0001

Untreated thyroid disease 23 (0.5) 165 (0.4) 0.13

Depression and/or anxiety 314 (6.7) 2 080 (4.4) < 0.0001

Systemic lupus erthematosus 1 (0.0) 5 (0.0) 0.52

Rheumatoid arthritis 9 (0.2) 64 (0.1) 0.34

Visits to a physician during year before pregnancy, no.

02 1 298 (27.6) 15 248 (32.4) 1.00

35 1 105 (23.5) 11 594 (24.6) 1.00

6 2 302 (48.9) 20 208 (43.0) < 0.0001

Different prescribers, no.

02 3 286 (69.8) 34 697 (73.7) 1.00

3 1 419 (30.2) 12 353 (26.3) < 0.0001

Visited emergency department or admitted to hospital duringyear before pregnancy

727 (15.4) 6 807 (14.5) 0.07

Obstetric complications

History of spontaneous abortion 73 (1.6) 706 (1.5) 0.78

History of planned abortion 179 (3.8) 1 441 (3.1) 0.005

Use of medications during year before pregnancy

Nonaspirin NSAIDs 833 (17.7) 7 028 (14.9) < 0.0001

Antidepressant agents 364 (7.7) 2 469 (5.2) < 0.0001

Systemic anti-infective agents 1 878 (39.9) 17 184 (36.5) < 0.0001

Systemic corticosteroids 108 (2.3) 982 (2.1) 0.34

Other 3 217 (68.4) 30 452 (64.7) < 0.0001

Note: NSAID = nonsteroidal anti-inflammatory drug, SD = standard deviation.*Unless otherwise indicated.Pearson

2test.

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we wished to assess several types o nonaspirinNSAIDs simultaneously, 10 controls were ran-domly selected or each case. Controls wereselected rom among pregnant women who didnot have a spontaneous abortion at the same ges-tational age o their matched case, but who wereat risk o having one, resulting in similar proba-bilities o exposure to medication. Controls werematched to the index date and gestational age othe case, because the risk o pregnancies endingin a loss is highly dependent on the gestationalage at which the pregnancy is recognized.

ExposureWe dened exposure to nonaspirin NSAIDs aseither having lled at least one prescription orany type o nonaspirin NSAID between the starto pregnancy and the index date, or as havinglled a prescription or a nonaspirin NSAIDbeore pregnancy, the duration o which over-lapped with the start o pregnancy. We only con-

sidered nonaspirin NSAIDs that were reim-bursed by the RAMQ drug plan during the studyperiod. Single exposure to nonaspirin NSAIDswas dened as having lled a prescription or atleast one dose o only one type o nonaspirinNSAID between the start o pregnancy and theindex date. Combination use o nonaspirinNSAIDs was dened as lling a prescription orat least one dose o two or more dierentnonaspirin NSAIDs rom the same or dierentclasses between the start o pregnancy and theindex date. In all analyses, the reerence categorywas dened as pregnant women not exposed tononaspirin NSAIDs between the start o preg-nancy and the index date.

In addition, we investigated the associationbetween recent exposure to nonaspirin NSAIDsand the risk o spontaneous abortion using thetwo weeks immediately beore the index date asour window or exposure. Finally, we examinedthe doseresponse relationship by classiying

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Table 3: Crude and adjusted odds ratios for the association between use of nonaspirin NSAIDs during pregnancy and having aspontaneous abortion (part 1 of 2)

OR (95% CI)

Variable Crude Adjusted*

No use of nonaspirin NSAIDs 1.00 1.00

Use of nonaspirin NSAIDs 3.06 (2.713.46) 2.43 (2.122.79)

Patient characteristics

Age, yr 1.04 (1.031.04) 1.04 (1.031.04)

Urban residence 1.07 (1.001.15) 1.00 (0.921.08)

Receiving social assistance 1.23 (1.161.31) 1.06 (0.990.13)Comorbidities during year before pregnancy

None 1.00 1.00

Diabetes mellitus 1.69 (1.322.15) 1.25 (0.961.63)

Cardiovascular disease 1.22 (0.971.54) 0.83 (0.641.07)

Asthma 1.19 (1.101.28) 1.03 (0.940.13)

Untreated thyroid disease 1.40 (0.902.16) 1.15 (0.721.84)

Depression and/or anxiety 1.55 (1.371.75) 1.25 (1.081.45)

Systemic lupus erythematosus 2.00 (0.2317.12) 0.54 (0.065.01)

Rheumatoid arthritis 1.41 (0.702.83) 1.12 (0.522.41)

Vsits to physicians during year before pregnancy, no.

02 1.00 1.00

35 1.12 (1.031.22) 1.12 (1.031.23)

6 1.34 (1.251.44) 1.31 (1.201.44)

Different prescribers, no.

02 1.00 1.00

3 1.21 (1.141.30) 0.93 (0.851.02)

Visited an emergency department or admitted to hospital during year beforepregnancy

No 1.00 1.00

Yes 1.08 (0.991.17) 0.88 (0.800.97)

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women according to the overall percent maxi-mum daily dose o nonaspirin NSAIDs they tookbetween the start o pregnancy and the indexdate. These doses were subdivided into our clin-ically relevant categories: 1%50%, 51%65%,66%80% and 81% or more. Women who didnot ll a prescription or a nonaspirin NSAIDbeore their index date were considered not tohave been exposed.

ConoundingWe considered variables associated with boththe exposure to nonaspirin NSAIDs and the risko spontaneous abortion as potential con-ounders. To assess conounding by indication,we considered variables potentially associatedwith the use o nonaspirin NSAIDs or their di-erent classes and types. These variables in-cluded sociodemographic characteristics on therst day o gestation, comorbidities in the yearbeore pregnancy (diabetes mellitus, cardiovas-

cular disease [hypertension, coronary athero-sclerosis, generalized and unspecied athero-sclerosis, primary cardiomyopathies and diusecardiac disease resulting rom disorders o theconnective tissue], asthma, untreated thyroiddisease [dened as having a diagnosis o hyper-or hypothyroidism without having lled a pre-scription or a corresponding medication],depression and/or anxiety, systemic lupus ery-thematosus and rheumatoid arthritis), use omedications suspected o increasing the risk ospontaneous abortion as well as use o othermedications in the year beore pregnancy, use ononaspirin NSAIDs beore pregnancy, use ohealth services in the year beore pregnancy andduring the period between the rst day o gesta-tion and the index date, and history o plannedor spontaneous abortion.

Statistical analysesTo describe the study population, we presented

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Table 3: Crude and adjusted odds ratios for the association between use of nonaspirin NSAIDs during pregnancy and having aspontaneous abortion (part 2 of 2)

OR (95% CI)

Variable Crude Adjusted

Use of medications during year before pregnancy

None 1.00 1.00

Nonaspirin NSAIDs 1.23 (1.131.33) 1.04 (0.951.13)

Antidepressant agents 1.51 (1.351.70) 0.98 (0.821.16)

Systemic anti-infective agents 1.16 (1.091.23) 1.07 (0.991.15)

Oral corticosteroids 1.10 (0.901.35) 0.85 (0.671.07)Other 1.18 (1.111.26) 1.02 (0.941.11)

Obstetric complications

None 1.00 1.00

Spontaneous abortions 1.04 (0.811.32) 0.90 (0.671.21)

Planned abortions 1.25 (1.071.47) 1.24 (1.031.51)

Prenatal visits before index date, no.

02 1.00 1.00

3 0.13 (0.120.15) 0.13 (0.120.14)

Visits to an obstetrician before index date, no.

No 1.00 1.00

Yes 1.02 (0.961.08) 1.19 (1.111.27)

Use of medications between conception and index dates

None 1.00 1.00

Antidepressant agents 2.01 (1.742.32) 1.54 (1.251.88)

Systemic anti-infective agents 1.12 (1.031.22) 0.98 (0.901.08)

Oral corticosteroids 2.14 (1.612.83) 1.60 (1.162.19)

Antiemetic agents 0.20 (0.170.23) 0.22 (0.190.26)

Other 1.74 (1.631.85) 1.70 (1.591.83)

Note: CI = confidence interval, NSAID = nonsteroidal anti-inflammatory drug, OR = odds ratio.*Odds ratios were adjusted for confounders listed in Methods.

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means or continuous variables and proportionsor dichotomous variables. Odds ratios (ORs)and 95% condence intervals (CIs) were calcu-lated using conditional logistic regression andadjusted or the potential conounders describedearlier. We conducted sensitivity analyses toevaluate whether our results were robust using a60-day window o exposure to nonaspirinNSAIDs beore the index date.

Results

A total o 67 160 pregnant women met our inclu-sion criteria. O those women, 4705 had a sponta-neous abortion, to whom 47 050 controls werematched according to index date and gestationalage. Overall, 352 women with a spontaneous abor-tion (7.5%) had lled one or more prescriptions ornonaspirin NSAIDs during pregnancy, comparedwith 1213 (2.6%) women among those who didnot have a spontaneous abortion (p < 0.05).

Women who had a spontaneous abortion wereslightly older, lived in an urban area, receivedsocial assistance and had more comorbidities inthe 12 months beore pregnancy than those whodid not. In addition, women who had a sponta-neous abortion used health care services more re-quently in the year beore pregnancy than thosewho did not (Table 1). Moreover, women who hada spontaneous abortion had ewer prenatal visitsand were taking more antidepressant, systemicanti-inective or other medications during preg-nancy compared with women who did not.

Naproxen was the most common nonaspirin

NSAID used during pregnancy among womenwho had a spontaneous abortion (2.8%, 133/4 705)and among those who did not (0.9%, 435/47 050),ollowed by ibuproen (1.3% [61/4 705] v. 0.6%[258/47 050]), roecoxib (0.8% [39/4 705] v. 0.3%[152/47 050]), dicloenac (0.7% [31/4 705] v.0.2% [82/47 050]) and celecoxib (0.6% [30/4 705]v. 0.2% [111/47 050]) (Table 2). Among our cases,0.6% o women (26/4 705) used two or morenonaspirin NSAIDs during pregnancy comparedwith 0.2% (118/47 050 o women in the controlgroup.

Adjusting or potential conounders, use o

nonaspirin NSAIDs during pregnancy was sig-nicantly associated with a 2.4-old increase inthe risk o spontaneous abortion (OR 2.43, 95%CI 2.122.79; 4705 cases, o which 352 wereexposed) compared with nonuse (Table 3). Ana-lyzing exposure to nonaspirin NSAIDs in thetwo weeks immediately beore the spontaneousabortion, we ound that the risk was higher (OR3.47, 95% CI 2.016.00; data not shown),although not signicantly dierent rom our pre-vious overall estimate. All types o nonaspirin

NSAIDs signicantly increased the risk o spon-taneous abortion (Table 2). The highest risk wasseen among women who used dicloenac alone(OR 3.09, 95% CI 1.964.87), whereas the low-est risk was seen among women who used roe-coxib alone (OR 1.83, 95% CI 1.242.70). How-ever, no doseresponse relationship was seenbased on the overall percent maximum dailydose o nonaspirin NSAIDs (Table 2).

Our sensitivity analysis based on a 60-daywindow o exposure resulted in the calculationo similar risk (data not shown).

Interpretation

Main ndingsThe use o nonaspirin NSAIDs during earlypregnancy is associated with statistically signi-cant risk (2.4-old increase) o having a sponta-neous abortion. We consistently saw that the risko having a spontaneous abortion was associated

with gestational use o dicloenac, naproxen,celecoxib, ibuproen and roecoxib alone or incombination, suggesting a class eect. We didnot see a doseresponse relationship.

Explanation and comparison with otherstudies

Our results agree with those o other studiesinvolving human subjects.3,4 Indeed, our studyagrees with Li and colleagues, who reported arisk o spontaneous abortion when nonaspirinNSAIDs were taken around the time o concep-tion (hazard ratio [HR] 5.6, 95% CI 2.313.7).4

However, our study did not replicate their ndingthat the association was even higher when expo-sure occurred immediately beore the sponta-neous abortion.4 This may be because the use ononaspirin NSAIDs immediately beore sponta-neous abortion was to relieve cramping, which isa precursor to the loss o pregnancy. I this werethe case, exposure would occur ater the event.This was not the case in our study, given thatboth o our estimates (use o nonaspirin NSAIDsat any time during pregnancy or in the twoweeks immediately beore spontaneous abortion)did not signicantly dier rom one another.

Although much remains unclear regarding themechanism o action, prostaglandins play a puta-tive role. The concentrations o prostaglandins inthe human decidua during early pregnancy arelower than those in the endometrium at any stageo the menstrual cycle, primarily due to adecrease in the synthesis o prostaglandins.11,12

Data suggest that pregnancy is maintained by amechanism that suppresses uterine synthesis oprostaglandins throughout gestation, and a deectin this inhibitory mechanism may be associated

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with early loss o pregnancy.12 Prostaglandins areprobably involved not only in the initial vascularchanges, but also throughout decidualization.13,14

Strengths and limitationsOur studys large sample size allowed us to eval-uate several types o nonaspirin NSAID and vari-ous dosages. We used accurate inormation onlled medications rather than rely on patientrecall. We also used physician-based diagnosesand records o procedures related to spontaneousabortion, which limited the potential or detectionand misclassication biases on outcome status.Gestational age, validated by Vilain and cowork-ers,9 was obtained rom hospital charts on theindex date, allowing us to calculate the exact tim-ing o exposure to nonaspirin NSAIDs duringpregnancy. We adjusted our results or indicationor the use o nonaspirin NSAIDs by adjustingor variables such as history o rheumatoid arthri-tis and systemic lupus, and or the duration o

exposure in the year beore pregnancy; we urtheradjusted or history o planned and spontaneousabortions. It is thereore unlikely that residualconounding by indication, i present, wouldexplain our results. Finally, the nested casecontrol design we used enabled us to select ourcontrols rom the same population as our cases,thereby limiting the potential or selection bias.

The potential limitations o our study includethe lack o data on exposure to over-the-counterormulations o nonaspirin NSAIDs during preg-nancy, in addition to the lack o inormation onthe indications or which nonaspirin NSAIDs

were used and on covariables such as smokingand body mass index (BMI).

The use o acetylsalicylic acid and over-the-counter nonaspirin NSAIDs were not accountedor, which could potentially lead to misclassica-tion o exposure. However, the extent o this bias islikely minimal. The only nonaspirin NSAID avail-able over-the-counter in Quebec is ibuproen, andwomen covered by the RAMQ drug plan had theopportunity to receive a prescription or the over-the-counter medication. In addition, cases and con-trols would have been equally likely to purchasethe over-the-counter medication. Hence, any such

misclassication would have been nondierential,resulting in an underestimation o risk.To our knowledge, smoking and maternal

BMI are not risk actors or spontaneous abor-tion,15 and are thus not conounders in our study.

Exposure data based on lled prescriptionsmight not necessarily refect actual intake o amedication. However, we believe that womenwho lled a prescription or nonaspirin NSAIDstook at least one dose, since the provincial drugplan requires that they make a copayment or their

medications. Given the design o our study, thislimitation is unlikely to invalidate our ndings.

Only clinically detected spontaneous abor-tions were included. Spontaneous abortions thatwere never detected by the women themselveswere excluded, as has been done in other similarstudies done thus ar.3,4 I nonaspirin NSAIDsincrease the risk o spontaneous abortions thatare not clinically detected, our ndings are con-servative and are underestimations o the truerisk. On the other hand, i nonaspirin NSAIDsare not associated with nonclinically detectedspontaneous abortions, there is no reason to be-lieve that misclassication would be dierentbetween cases and controls, resulting in nondi-erential misclassication.

We cannot rule out the possibility o chancendings or 5.0% o our statistically signicantassociations due to the number o comparisonsmade in our study.

Finally, our study population covered only

36% o pregnant women in Quebec; althoughthis will not aect the validity o our results, itmight alter their ability to be generalized to thewider population.

Conclusion and implications or utureresearch

Women who were exposed to any type anddosage o nonaspirin NSAID during early preg-nancy were more likely to have a spontaneousabortion. Given that the use o nonaspirinNSAIDs during early pregnancy has been shownto increase the risk o major congenital malor-

mations1 and that our results suggest a classeect on the risk o clinically detected sponta-neous abortion, nonaspirin NSAIDs should beused with caution during pregnancy. Futureresearch should ocus on determining exactmechanisms o action.

Reerences1. Oori B, Oraichi D, Blais L, et al. Risk o congenital anomalies in

pregnant users o non-steroidal anti-infammatory drugs: anestedcasecontrol study. Birth Deects Res B Dev Reprod Toxicol2006;77:268-79.

2. Olesen C, Steensen FH, Nielsen GL, et al. Drug use in rstpregnancy and lactation: a population-based survey among Dan-ish women. The EUROMAP group.Eur J Clin Pharmacol 1999;55:139-44.

3. Nielsen GL, Sorensen HT, Larsen H, et al. Risk o adverse birthoutcome and miscarriage in pregnant users o non-steroidal anti-infammatory drugs: population based observational study andcasecontrol study.BMJ2001;322:266-70.

4. Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-infam-matory drugs during pregnancy and risk o miscarriage: popula-tion based cohort study.BMJ2003;327:368.

5. Nakhai-Pour HR, Brard A. Major malormations ater rsttrimester exposure to aspirin and NSAIDs.Expert Review 2008;1:605-16.

6. Essebag V, Genest J Jr, Suissa S, et al. The nested casecontrolstudy in cardiology.Am Heart J2003;146:581-90.

7. Brard A, Lacasse A. Validity o perinatal pharmacoepidemio-logic studies using data rom the RAMQ administrative data-base. Can J Clin Pharmacol 2009;16:e360-9.

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8. Tamblyn R, Lavoie G, Petrella L, et al. The use o prescriptionclaims databases in pharmacoepidemiological research: theaccuracy and comprehensiveness o the prescription claims data-base in Quebec.J Clin Epidemiol 1995;48:999-1009.

9. Vilain A, Otis S, Forget A, et al. Agreement between administrativedatabases and medical charts or pregnancy-related variables amongasthmatic women. Pharmacoepidemiol Drug Sa2008;17:345-53.

10. Levy AR, Mayo NE, Grimard G. Rates o transcervical andpertrochanteric hip ractures in the province o Quebec, Canada,19811992.Am J Epidemiol 1995;142:428-36.

11. Maathuis JB, Kelly RW. Concentrations o prostaglandins F2 andE2 in the endometrium throughout the human menstrual cycle,ater the administration o clomiphene or an oestrogenprogesto-gen pill and in early pregnancy.J Endocrinol 1978;77:361-71.

12. Abel MH, Smith SK, Baird DT. Suppression o concentration oendometrial prostaglandin in early intrauterine and ectopic preg-nancy in women.J Endocrinol 1980;85:379-86.

13. Tobert JA. A study o the possible role o prostaglandins indecidualization using a nonsurgical method or the instillation ofuids into the rat uterine lumen.J Reprod Fertil 1976;47:391-3.

14. Kennedy TG, Lukash LA. Induction o decidualization in rats bythe intrauterine inusion o prostaglandins. Biol Reprod1982;27:253-60.

15. Nakhai-Pour HR, Broy P, Brard A. Use o antidepressants dur-ing pregnancy and the risk o spontaneous abortion. CMAJ2010;182:1031-7.

Afliations: From the Faculty o Pharmacy (Nakhai-Pour,Brard), University o Montreal, Montral, Que.; theResearch Center (Nakhai-Pour, Broy, Sheehy, Brard), Cen-tre hospitalier universitaire Ste-Justine, Montral, Que.; andcole Nationale de la Statistique et de lAnalyse de lInor-mation (Broy), Rennes, France.

Contributors: Hamid Reza Nakhai-Pour and Anick Brardconceived o and designed the study and drated the manu-script. Anick Brard acquired the data and supervised thestudy; she had ull access to all o the data and takes respon-

sibility or the integrity o the data and the accuracy o thedata analysis. Hamid Reza Nakhai-Pour, Perrine Broy, OdileSheehy and Anick Brard analyzed and interpreted the data.Odile Sheehy and Anick Brard provided administrative,technical and material support. Hamid Reza Nakhai-Pour,Perrine Broy and Odile Sheehy perormed the statisticalanalyses. All o the authors critically revised the manuscriptor important intellectual content and approved the nal ver-sion submitted or publication.

Funding: This study was supported by the Fonds de larecherche en sant du Qubec and the Rseau Qubcois derecherche sur lusage des mdicaments.

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