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Research www.AJOG.orgborn (fetal deaths at 20 weeks gesta-tion), and prenatally diagnosed and elec-tively terminated cases (AR, CA, GA, IA,TX); 1 state included only liveborn andstillborn cases (MA), and 2 states in-cluded only liveborn cases (NJ, NY).Liveborn control infants without major

nters of Excellence Award No.U50/CCU913241.

findings and conclusions in this report are those of the authors and do not necessarilyresent the views of the Centers for Disease Control and Prevention.prints: Suzan L. Carmichael, PhD, March of Dimes Foundation, 5700 Martin Luther King Jr.y, Oakland, CA; SCarmichael@marchofdimes.com

2-9378/$32.00 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.05.046sion of a review of case reports thatre published in 1995 that, used during

from a recent, largecase-control study tha

m the March of Dimes Foundation/California Department of Healthth Defects Monitoring Program, Berkeley, CA (Drs Carmichael andne Epidemiology Center, Boston University, Boston, MA (Dr Werlernter on Birth Defects and Developmental Disabilities, Centers for Divention, Atlanta, GA (Dr Rasmussen); and Childrens Hospital Oakltitute, Oakland, CA (Dr Lammer).

ceived Dec. 1, 2006; accepted May 30, 2007.

ported by a cooperative agreement from the Centers for Disease ContrSee Journal Club, page 683

DEpulation-basedas conducted in

fects Prevention Study, amultistate case-control study of 30 different birth de-fects. This studywas an approved activityof the institutional review boards of theparticipating study centers and the Cen-ters for Disease Control and Prevention.Detailed studymethods anddescriptionsof the surveillance systems in the 8 statesthat contributed data to this analysishave been published.14,15 In brief, 5 of

rvices, Californiaw and Ms Ma);he Nationale Control andResearch

nd Prevention,BSTETRICS

aternal corticosteroid use and orofacial cleftszan L. Carmichael, PhD; Gary M. Shaw, DrPH; Chen Ma, MA; Martha M. Werler, ScD, MPH; Sonja A. Rasmussen, MD;ward J. Lammer, MD; for the National Birth Defects Prevention Study

JECTIVE: The purpose of this study was to examine whether mater-corticosteroid use during pregnancy is associated with delivering

infant with an orofacial cleft.

UDY DESIGN: This study included data on deliveries from the Na-al Birth Defects Prevention Study, which is a population-basede-control study. Exposures were assessed by telephone interviewsmothers of 1141 cases with cleft lip cleft palate (CLP), 628 withft palate (CP), and 4143 controls.

SULTS: Mothers of 33 infants with CLP (2.9%), mothers of 6 infantsh CP (1.0%), and 72 control subjects (1.7%) reported corticoste-

roid use from 4 weeks before through 12 weeks after conception. Thecrude odds ratio for any vs no use was 1.7 (95% CI, 1.1-2.6) forCLP and 0.5 (0.2-1.3) for CP. When analyzed by route of administra-tion and medication components, odds ratios for CLP tended to beelevated, and odds ratios for CP tended to be close to 1.

CONCLUSION: Our results suggest a moderately increased risk of CLPamong women who use corticosteroids during early pregnancy.

Key words: corticosteroid, orofacial cleft

this article as: Carmichael SL, Shaw GM, Ma C, et al. Maternal corticosteroid use and orofacial clefts. Am J Obstet Gynecol 2007;197:585.e1-585.e7.

orticosteroids (ie, glucocorticoids)are a class of medications that have

tiinflammatory and immune-sup-ssive properties that make them use-in the treatment of many conditions,luding asthma, rheumatoid arthritis,ergic reactions, and eczema. Further,thylprednisolone has been recom-nded as an alternative treatment forperemesis gravidarum during earlygnancy.1 Corticosteroids cause a va-ty of malformations in several differ-t animal models.2,3 Despite the con-

pregnancy, corticosteroids present min-imal, if any, risk to the fetus,4 several hu-man epidemiologic studies have sug-gested that use during early pregnancy isassociated with a 3- to 6-fold increasedrisk of orofacial clefts,5-12 with oneexception.13

This study examined whether womenwho reported corticosteroid use duringpregnancy were more likely to deliver aninfant with an orofacial cleft thanwomen who did not report corticoste-roid use; the data that were used was

the United States. The study expands onmost previous case-control studiesthrough its ability to better analyze typesof corticosteroid medications and itsmore detailed information on timing ofexposures.

MATERIALS AND METHODSThis analysis included data on deliveriesthat occurred during or after October1997 and that had estimated dates of de-livery during or before December 2002potw

and were part of the National Birth De-

the 8 states ascertained liveborn, still-

SeSha); tseasand

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CEMBER 2007 American Jth defects were selected randomly

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58m birth certificates (GA [2001-2002],, MA, NJ) or from birth hospitals (AR,, GA [1997-2000], NY, TX) that re-cted the populations fromwhich casesre derived. Because the study focuseddefects of unknown cause, infants

th recognized or strongly suspectedgle-gene disorders or chromosomalnormalities were excluded.ases included infants or fetuses whore born with cleft lip with or withoutft palate (CLP) or cleft palate (CP), asfirmed by clinical description or sur-al or autopsy report. Each case re-ved an additional review by 1 clinicaleticist (S.A.R.) to ensure that casesm each study center met standard el-bility criteria. This geneticist also clas-ed each case as isolated if there was noditional major unrelated defect or asltiple if there was at least 1 accompa-ing major unrelated defect.16 Infantsose cleftswere believed to be the resultanother defect (eg, holoprosencephalyamniotic band sequence) were ex-ded from this analysis. CLP caseswerether classified as bilateral, unilateral,tral, or not otherwise specified.aternal interviews were conducted

th a standardized, computer-basedephone questionnaire in English oranish, no earlier than 6 weeks and noer than 24 months after the infantsimated date of delivery (EDD). FinalD was based on mothers self-report;unknown, EDD was estimated fromormation in themedical record (2%subjects). Participation rates for thedywere 76%among casemothers and% among control mothers. The meane from delivery to interview was 10.4nths for casemothers and 8.7monthscontrol mothers.xposures to corticosteroid medica-ns were assessed by asking womenether they experienced various typesillnesses and injuries (eg, respiratoryesses; infections) and what medica-ns they used to treat them. Womeno described the specific illness or in-y they experienced. In a final section,men reported use of any other medi-ion not reported in the preceding ill-ss/injury-specific sections; indications not recorded in this section. For each

dication, women reported start and com

5.e2 American Journal of Obstetrics & Gynecologyp dates of use and frequency of use.omen who knew only the start date orp date of use, but not both, were askedreport duration of use.Medication ex-sures were assessed from 12 weeks be-e conception through the date of de-ery.Date of conceptionwas derived bytracting 266 days from the womansD. A drug code was assigned to eachdication exposure by a central codingility, with the Slone Epidemiologynter Drug Dictionary. These codesre used to identify the primary com-nents in each medication. Route ofministration (eg, topical, systemic)s assigned based on exact wordingm the mothers report or known for-lation of the medication. Indications assigned based on injury or illnessorted in conjunction with the corti-teroid medication.he following covariates were choseninclusion in multivariable models aori, given that they may be associatedth risk of orofacial clefts and reportedticosteroid use: maternal race-eth-ity (non-Hispanic white, non-His-nic black, Hispanic, other), educationtegorized as less than high schoolduation, equal to high school gradu-on, greater than high school gradua-n), intake of folic acid-containingplements or smoking during thenth before or the first 3 months ofgnancy, and study center.LP and CP were analyzed separately.

e first examined the association ofks of clefts with any vs no corticoste-d use during the periconceptional pe-d (ie, 4weeks before through 12weekser conception). We initially examineds window of time, which both pre-es and extends beyond the time of lipd palate formation (lip formation ispleted during weeks 5-7 after con-tion, and palate formation is com-ted during weeks 8-12 after concep-n), because of potential misreportingdates of exposure and because of po-tial effects of corticosteroid medica-ns that extend beyond their actual pe-d of intake (eg, adrenal suppression).e then examined associations withre specific timewindows of exposure,te of administration, andmedication

ponents. We also assessed associa- an

DECEMBER 2007ns with use that began later than 12eks after conception (ie, after devel-ment of the lip and palate would haveen completed) to help assess potentialall bias. Odds ratios (ORs) were esti-ted only if there were at least 2 ex-sed cases and 2 exposed control sub-ts in a particular comparison. Toimate relative risks, maximum likeli-od estimates of ORs and their corre-nding 95%confidence intervals (CIs)re calculated from logistic regressiondels with SAS software (v 9.1; SAStitute Inc, Cary, NC).17,18 We reex-ined final estimates after adjustmentthe covariates listed earlier and afterludingmultiple cases, cases without agnostic code for Pierre Robin se-ence in their abstracted medicalord, and subjects with no family his-y of orofacial clefts in a parent orling.

SULTSe interviewed mothers of 1141 infantsth CLP, 628 infants with CP, and 4143trol infants. Most mothers of controlants were non-Hispanic white (60%),ended college (58%), took folic acid-taining supplements (86%), and didt smoke (81%; Table 1). Mothers wereatively evenly distributed across theters.n total, mothers of 33 infants withP (2.9%), 6 infants with CP (1.0%),d 72 control infants (1.7%) reportedy corticosteroid medication use dur-the 4 weeks before through 12 weekser conception (Table 2). The OR fory vs no corticosteroid exposure was(95% CI, 1.1-2.6) for CLP and 0.5% CI, 0.2-1.3) for CP. The ORs forsubphenotypes of CLP (unilateral,

ateral, central, and not otherwisecified phenotypes) were similar to thes for all CLP cases grouped togetherta not shown). TheOR forCPwas thee when restricted to cases withoutrre Robin (4 exposed cases and 460exposed cases).hen analyzed by route of adminis-

tion and specific component, ORs forP were 1.5, with the exception ofticasone (OR, 1.3; 95% CI, 0.6-2.9)

d topical preparations (OR, 0.9; 95%

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ws of exposure during the pericon-tional period were conducted forP, but not CP, given that only 6 CPes were exposed (Table 3). Expo-res that occurred only during the 4eks before conception were not as-iated with significantly increasedk (OR, 2.3; 95% CI, 0.8-7.0). Preg-ncy exposures that occurred duringth weeks 1-4 and 5-8 after concep-n, but not during weeks 9-12, wereociated with the highest increase ink (OR, 7.3; 95% CI, 1.8-29.4). Preg-ncy exposures that occurred duringeks 1-4, 5-8, and 9-12 after concep-n (ie, exposures occurred duringh of these 3 time periods) were notociated with significantly increasedk (OR, 1.4; 95%CI, 0.8-2.6).We alsode the less restrictive comparison ofy vs no exposure during the first 8eks after conception to capture allosures during this time period (OR,; 95% CI, 1.1-2.9).eparate analyses by indication weret conducted, because indication wast specified in most exposed cases/33) and control subjects (38/72) andcause the reported indications wereerse, especially within subgroups onbasis of timing.xposures that began after 12 weeksconception were not associated withreased risk of CLP and with slightlyreased risk of CP, but estimatesre imprecise. The OR for use thatgan from 13-23 weeks after concep-n was 0.6 (95% CI, 0.2-1.9) for CLPd 1.4 (95% CI, 0.5-3.8) for CP; thefor use that began 23 weeks after

nception was 0.9 (95% CI, 0.4-2.0)CLP and 1.5 (95% CI, 0.7-3.5) for. The reference group for these com-risons included subjects who did note corticosteroids from 4 weeks be-e conception through the time oflivery.nalyses that were adjusted for all co-iates were very similar to the unad-ted results (data not shown). Resultsm analyses that excluded nonisolated

P cases (n 138) and nonisolated CP wees (n 117) and subjects with a fam-history of a cleft in a parent or siblingCLP cases, 35 CP cases, and 17 con-l subjects) alsowere very similar to theults without these exclusions. For ex-ple, the ORs for any vs no use from 4

ABLE 1haracteristics of mothers of 1141 iithout CLP, 628 infants with CP aloontrol infants

ariable

ace/ethnicity.................................................................................................................

Non-Hispanic white.................................................................................................................

Non-Hispanic black.................................................................................................................

Hispanic.................................................................................................................

Other.................................................................................................................

Unknown.........................................................................................................................

ducation.................................................................................................................

High school graduation.................................................................................................................

High school graduation.................................................................................................................

1-3 yrs of college.................................................................................................................

4 yrs of college.................................................................................................................

Unknown.........................................................................................................................

moking.................................................................................................................

Any.................................................................................................................

None.................................................................................................................

Unknown.........................................................................................................................

ntake of folic acid-containing supplements.................................................................................................................

Any.................................................................................................................

None.................................................................................................................

Unknown.........................................................................................................................

tudy site.................................................................................................................

Arkansas.................................................................................................................

California.................................................................................................................

Georgia.................................................................................................................

Iowa.................................................................................................................

Massachusetts.................................................................................................................

New Jersey.................................................................................................................

New York.................................................................................................................

Texas.........................................................................................................................

Percentages may not add to 100% because of rounding.

During the month before or the first 3 months of pregnancy.

armichael. Maternal corticosteroid use and orofacial clefts. Am Jeks before through 12 weeks after the

DECEMBER 2007 American Jception were 1.7 (95% CI, 1.1-2.7)CLP and 0.5 (95%CI, 0.2-1.2) for CPer adjustment for all covariates, andORs were 1.5 (95% CI, 1.0-2.4) forP (25 exposed cases) and 0.5 (95%CI,-1.3) for CP (4 exposed cases) after

nts with cleft lip with or, and 4143 nonmalformed

ercent (n)*

LP CP Control

...........................................................................................................

62 (708) 68 (428) 60 (2477)...........................................................................................................

6 (70) 7 (41) 12 (498)...........................................................................................................

26 (293) 18 (116) 23 (940)...........................................................................................................

6 (69) 7 (42) 5 (217)...........................................................................................................

1 (1) 1 (1) 1 (11)...........................................................................................................

...........................................................................................................

21 (245) 17 (104) 16 (679)...........................................................................................................

28 (317) 26 (163) 25 (1032)...........................................................................................................

25 (287) 29 (183) 27 (1113)...........................................................................................................

25 (282) 27 (172) 31 (1277)...........................................................................................................

1 (10) 1 (6) 1 (42)...........................................................................................................

...........................................................................................................

26 (291) 24 (149) 19 (801)...........................................................................................................

74 (842) 76 (475) 80 (3315)...........................................................................................................

1 (8) 1 (4) 1 (27)...........................................................................................................

...........................................................................................................

83 (952) 85 (533) 86 (3543)...........................................................................................................

16 (184) 15 (93) 14 (588)...........................................................................................................

1 (5) 1 (2) 1 (12)...........................................................................................................

...........................................................................................................

10 (117) 10 (63) 12 (503)...........................................................................................................

17 (198) 12 (76) 15 (604)...........................................................................................................

11 (123) 14 (89) 11 (465)...........................................................................................................

12 (136) 10 (61) 12 (491)...........................................................................................................

13 (150) 18 (113) 13 (537)...........................................................................................................

10 (118) 12 (74) 14 (578)...........................................................................................................

10 (118) 12 (74) 11 (453)...........................................................................................................

16 (181) 12 (78) 12 (512)...........................................................................................................

tet Gynecol 2007.conforafttheCL0.2

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58MMENTthis study, maternal periconceptionalticosteroid use was associated with aderately increased risk of CLP, but not. Most of the comparisons by route ofinistration and for specific compo-

ABLE 2ssociation of risk of orofacial cleftedications from 4 weeks before thomponent corticosteroid

oute of administration and component

ny use.........................................................................................................................

ny systemic use.........................................................................................................................

rednisone.........................................................................................................................

ny nasal spray/inhaled use.........................................................................................................................

eclomethasone.........................................................................................................................

udesonide.........................................................................................................................

luticasone.........................................................................................................................

riamcinolone.........................................................................................................................

ny topical use.........................................................................................................................

ther/not otherwise specified use.........................................................................................................................

Three cases and 4 control subjects were included in 1 com

Reference groups for the comparisons included 1108 infants w

armichael. Maternal corticosteroid use and orofacial clefts. Am J

ABLE 3ssociation of risk of CLP among ofxposure time period

ny exposure from 4 wks before conception th12 wks after conception

.........................................................................................................................

xposed only during 4 wks before conception.........................................................................................................................

regnancy exposure only during wks 1-4 afterconception

.........................................................................................................................

regnancy exposure only during wks 5-8 afterconception

.........................................................................................................................

regnancy exposure only during wks 9-12 afteconception

.........................................................................................................................

regnancy exposure during wks 1-4 and 5-8 aconception

.........................................................................................................................

regnancy exposure during wks 5-8 and 9-12conception

.........................................................................................................................

regnancy exposure during wks 1-4, 5-8, andafter conception

.........................................................................................................................

ny exposure during wks 1-4 or 5-8 afterconception

.........................................................................................................................

Reference groups for all comparisons included 1108 cases andhere were at least 2 exposed cases and 2 exposed controls.armichael. Maternal corticosteroid use and orofacial clefts. Am J Obs

5.e4 American Journal of Obstetrics & Gynecologyt medications yielded ORs for CLP of.5; however, these comparisonshad lesscision than the overall results, becausemaller sample size.Only topicalusewast associated with increased risk of CLP.corticosteroid medications are associ-

mong offspring born to women whogh 12 weeks after conception, by r

CLP (n)* CP (n)* Control (n)*

33 6 72.........................................................................................................................

9 2 16.........................................................................................................................

8 2 11.........................................................................................................................

19 5 47.........................................................................................................................

5 2 11.........................................................................................................................

3 2 4.........................................................................................................................

8 0 23.........................................................................................................................

5 1 9.........................................................................................................................

2 0 8.........................................................................................................................

4 0 5.........................................................................................................................

on because of maternal intake of multiple medications with diffe

LP, 622 infants with CP, and 4071 control subjects with no expo

tet Gynecol 2007.

ring born to women who used cortiCLP (n) Contr

h 33 72

.........................................................................................................................

5 8.........................................................................................................................

3 8

.........................................................................................................................

1 1

.........................................................................................................................

2 11

.........................................................................................................................

6 3

.........................................................................................................................

r 1 2

.........................................................................................................................

2 15 39

.........................................................................................................................

26 53

.........................................................................................................................

1 controls with no exposure from 4 weeks before through 12 wtet Gynecol 2007.

DECEMBER 2007d with at least some systemic absorp-n, regardless of the route of administra-n.19,20 Topical preparations are likely toult in lower systemic levels than othertesofadministration,butabsorptionofseproductsvarieswidely,dependingon

sed maternal corticosteroidte of administration and

OR (95% CI)

CLP CP

1.7 (1.1-2.6) 0.5 (0.2-1.3)...........................................................................................................

2.1 (0.9-4.7) 0.8 (0.2-3.6)...........................................................................................................

2.7 (1.1-6.7) 1.2 (0.3-5.4)...........................................................................................................

1.5 (0.9-2.5) 0.7 (0.3-1.8)...........................................................................................................

1.7 (0.6-4.8) 1.2 (0.3-5.4)...........................................................................................................

2.8 (0.6-12.3) 3.3 (0.6-17.9)...........................................................................................................

1.3 (0.6-2.9) ...........................................................................................................

2.0 (0.7-6.1) ...........................................................................................................

0.9 (0.2-4.3) ...........................................................................................................

2.9 (0.8-11.0) ...........................................................................................................

routes of administration or specific components.

from 4 weeks before through 12 weeks after conception.

steroids, by timing of exposure(n) Odds ratio (95% CI)*

1.7 (1.1-2.6)

...........................................................................................................

2.3 (0.8-7.0)...........................................................................................................

1.4 (0.4-5.2)

...........................................................................................................

...........................................................................................................

0.7 (0.1-3.0)

...........................................................................................................

7.3 (1.8-29.4)

...........................................................................................................

...........................................................................................................

1.4 (0.8-2.6)

...........................................................................................................

1.8 (1.1-2.9)

...........................................................................................................

after conception; odds ratios were estimated only iffsp cools

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www.AJOG.org Obstetrics Researchtors such as formulation and frequencyuse.ost,5-10 but not all,13 previous epi-

miologic studies of maternal corti-steroid intake and risk of clefts haveorted increased risks. Only 2 previ-

ABLE 4ummary of previous epidemiologicf orofacial clefts

tudy Study design

zeizel &Rockenbauer5

Population-based case-control study inHungary

.........................................................................................................................

.........................................................................................................................

odriguez-Pinilla &Martinez-Frias6

Hospital-based case-control study inSpain

.........................................................................................................................

allen et al13 Swedish birth registrycohort

.........................................................................................................................

armichael &Shaw7

Population-based case-control study inCalifornia; isolatedcases only

.........................................................................................................................

dwards et al8 Hospital-based case-control study inAustralia

.........................................................................................................................

radat et al9 9 registries of drug-exposed, malformedinfants (MADRE)

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

allen10 Swedish birth registrycohort

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

.........................................................................................................................

armichael. Maternal corticosteroid use and orofacial clefts. Am Js studies involved 10 exposed emes,9,10 so most studies have notmpared risks on the basis of differentdes of intake. Specific analyses bying or duration of intake or by spe-c phenotypes were also limited.5,10

summary, a clear pattern has not

dies of maternal corticosteroid inta

ode or component

Relative risk estimate

All clefts

ral

.........................................................................................................................

intment.........................................................................................................................

ystemic 5.2 (1.5-17.1); 5

.........................................................................................................................

udesonide 1.2 (0.3-3.1); 4

.........................................................................................................................

ny

.........................................................................................................................

opical 13.2 (1.7-586); 9

.........................................................................................................................

ny 1.1 (0.7-1.5); 37

.........................................................................................................................

testinal/antiinflammatoryagents

0.6 (0.1-2.9); 2

.........................................................................................................................

ermatologic 0.5 (0.2-1.6); 3.........................................................................................................................

ystemic, plain 1.3 (0.7-2.2); 15.........................................................................................................................

ystemic drugs incombination

2.1 (1.0-4.3); 9

.........................................................................................................................

asal preparations 1.7 (0.6-4.3); 5.........................................................................................................................

haled antiasthmatics 0.6 (0.2-1.7); 4.........................................................................................................................

ny All: 1.4 (1.0-2.0); 32

.........................................................................................................................

Isolated: 1.3 (0.9-2.0); 24

.........................................................................................................................

Nonisolated: 1.9(0.8-3.8); 8

.........................................................................................................................

ystemic 1.9 (0.8-4.0); 7.........................................................................................................................

ntiasthmatic 1.2 (0.7-1.9); 16.........................................................................................................................

ose drops 1.4 (0.6-2.9); 7.........................................................................................................................

opical 2.0 (0.6-5.2); 4tet Gynecol 2007.erged with regard to factors such as thi

DECEMBER 2007 American Jte of administration, specific med-tion, components, timing, and du-ion of intake, or by specific pheno-e, in large part because these factorsve not been analyzed by most previ-s studies. The available literature on

during early pregnancy and risk

5% CI); no. of exposed infants

P CP

.9 (1.7-20.3); 3

...........................................................................................................

.2 (1.5-12.0); 4...........................................................................................................

.9 (2.0-37.9); 4

...........................................................................................................

...........................................................................................................

.3 (1.1-17.2); 6 5.3 (1.1-26.5); 3

...........................................................................................................

.7 (1.4-537); 5 12.0 (1.1-600); 4

...........................................................................................................

.3 (0.9-1.9); 30 0.6 (0.3-1.5); 6

...........................................................................................................

3.0 (0.7-13.1); 2

...........................................................................................................

.7 (0.2-2.4); 3 0...........................................................................................................

.8 (1.0-3.1); 13 0.3 (0.04-1.5); 1...........................................................................................................

.6 (1.2-5.7); 7 1.2 (0.3-4.9); 2

...........................................................................................................

.5 (1.0-6.3); 5 0...........................................................................................................

.7 (0.2-2.2); 3 0.6 (0.1-5.1); 1...........................................................................................................

: 1.3 (0.7-2.0); 17 All: 1.7 (1.0-2.8); 15

...........................................................................................................

lated: 1.1 (0.6-1.9); 13

Isolated: 1.8 (0.9-3.2); 11

...........................................................................................................

...........................................................................................................

...........................................................................................................

...........................................................................................................

...........................................................................................................cascomotimcifiIn

rouicarattyphaou

......... .........

O 4......... .........

S 8

......... .........

B

......... .........

A 4

......... .........

T 11

......... .........

A 1

......... .........

In 0

......... .........

D 0......... .........

S 1......... .........

S 2

......... .........

N 2......... .........

In 0......... .........

A All

......... .........

Iso

......... .........

......... .........

S......... .........

A......... .........

N......... .........

TObss topic is summarized in Table 4.

ournal of Obstetrics & Gynecology 585.e5

FroielsmoimbyingtiewisiobatrenopaoloCoconingrupsueepS

ulaconmispevarstudatheontomatioknveravamumeantiocoscauusetiocifidaThgivanpomeemwaCLan

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REF1. SGoin t

2. Rato1983. MThehumArc4. Fcor51:5. Cbastial56:6. Rcoscas7. CsteGe8. EconuseAm9. PRoterBirt67:10.lip/Cle11.masur19912.al.ticometolo13.italbud19914.al.Pub15.Coreption16.al.tionfec17.abidat19918.Be19.Per17-

Research Obstetrics www.AJOG.org

58etal endogenous levels of corticoste-ds are much lower than maternal lev-so that even minor passage fromther to fetus could have substantialpact on fetal levels.21 The mechanismswhich corticosteroidsmay cause cleft-are uncertain, but several possibili-

s exist. Corticosteroids are associatedth maternal and fetal adrenal suppres-n and altered sex steroid synthesis andlance, even after relatively short-termatment.22-28 They are required forrmal growth and differentiation of thelate epithelial cells, but supraphysi-gic doses disrupt this process.2,29

rticosteroids can reduce the collagentent of connective tissue by inhibit-collagen synthesis, which could dis-t cell-cell interaction and tissue-tis-interactions, such as between

ithelium and mesenchyme.29

trengths of this study include its pop-tion-based design and its ability toduct detailed analyses by route of ad-nistration and timing of intake, bycific phenotype, and by potential co-iates. However, even as 1 of the largerdies of corticosteroids and clefts tote, sample size was limited for some ofse specific comparisons. Informationdosewas not available, and our abilityconduct analyses based on underlyingternal conditions was limited. Indica-ns for corticosteroid use were un-own for most women and were di-se amongwomen forwhom theywereilable, as would be expected given theltiple indications for corticosteroiddication use. Our ability to conductalyses based on other types of medica-ns, taken in combination with corti-teroids, was also limited, again be-se of the fact that corticosteroids ared for such a wide variety of indica-ns. Our ability to further analyze spe-c phenotypes was limited, becauseta were sparse (eg, Robin sequence).e retrospective design was a necessity,en the relative rarity of the outcomed the exposure, but it did result in thessibility of maternal bias in recall ofdication use. Use that began after thebryologically relevant time periods not associated with increased risk ofP, which argues against recall bias as

alternative explanation for our find-

ranAm

5.e6 American Journal of Obstetrics & Gynecologys. However, use that occurred onlyring the 4 weeks before conceptions associated with increased risk. Thisservation could be because of recalls; alternatively, the effects of cortico-roid medications may extend beyondir actual period of intake. Prospec-ely collected information was notilable to verify maternal recall. In thisdy, 1.7% of control mothers reportedticosteroid use during the 4weeks be-e conception or during pregnancy;s percentage is comparable with whats been reported by other studies.5,10 Astantial proportion of mothers ofes (24%) and control subjects (32%)not participate; the generalizability

our results to the study population isrefore uncertain.he current literature points toward aderately increased risk of cleftsong women who take corticosteroiddications during early pregnancy.ven that a relatively small percentagewomen use corticosteroids duringgnancy and the moderate increase ink, corticosteroid use likely accountsonly a small fraction of clefts.reviously published information re-ding potential differences in risks thatassociated with particular types ofticosteroids, timing of exposure, orenotypes is limited. Information onassociation of corticosteroidmedica-ns with other birth defects is evenre limited. Further studies are neededprovide this information. In turn, atter understanding of the potentialatogenicity of corticosteroids will al-clinicians and pregnant women to

ke more informed decisions regard-the use of these important drugs dur-pregnancy. f

NOWLEDGMENTding of drug information in the National Birthfects Prevention Study used the Slone Epi-iology Center Drug Dictionary, under li-se from the Slone Epidemiology Center atston University.

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domized, double-blind, controlled study.J Obstet Gynecol 1998;179:921-4. J In

DECEMBER 2007owland J, Hendrickx A. Corticosteroid ter-genicity. Adv Vet Sci Comp Med3;27:99-128.ontenegro MA, Palomino H, Palomino HM.influence of earthquake-induced stress onan facial clefting and its simulation in mice.h Oral Biol 1995;40:33-7.raser FC, Sajoo A. Teratogenic potential ofticosteroids in humans. Teratology 1995;45-6.zeizel AE, Rockenbauer M. Population-ed case-control study of teratogenic poten-of corticosteroids. Teratology 1997;

335-40.odriguez-Pinilla E, Martinez-Frias M. Corti-teroids during pregnancy and oral clefts: ae-control study. Teratology 1998;58:2-5.armichael SL, Shaw GM. Maternal cortico-

roid use and orofacial clefts. Am J Mednet 1999; 86:242-4.dwards MJ, Agho K, Attia J, et al. Case-trol study of cleft lip or palate after maternalof topical corticosteroids during pregnancy.J Med Genet 2003;120:459-63.radat P, Robert-Gnansia E, Di Tanna GL,

sano A, Lisi A, Mastroiacovo P. First trimes-exposure to corticosteroids and oral clefts.h Defects Res Clin Mol Teratol 2003;968-70.Kallen B. Maternal drug use and infant cleftpalate with special reference to corticoids.ft Palate Craniofac J 2003;40:624-8.Robert E, Vollset S, Botto L, et al. Malfor-tion surveillance and maternal drug expo-e: the MADRE project. Risk Safety Med4;6:78-118.Park-Wyllie L, Mazzotta P, Pastuszak A, etBirth defects after maternal exposure to cor-steroids: prospective cohort study andta-analysis of epidemiological studies. Tera-gy 2000;62:385-92.Kallen B, Rydhstroem H, Aberg A. Congen-malformations after the use of inhaledesonide in early pregnancy. Obstet Gynecol9;93:392-5.Yoon PW, Rasmussen SA, Lynberg MC, etThe National Birth Defect Prevention study.lic Health Rep 2001;116(suppl 2):32-40.National Birth Defects Prevention Network.ngenital malformations surveillance report: aort from the National Birth Defects Preven-Network. Teratology 2000;61:33-158.Rasmussen SA, Olney RS, Holmes LB, etGuidelines for case classification for the Na-al Birth Defects Prevention Study. Birth De-ts Res Clin Mol Teratol 2003;67:193-201.Selvin S. Measures of risk: rates and prob-lities: statistical analysis of epidemiologica. New York: Oxford University Press;1:1-35.Selvin S. Practical biostatistical methods.lmont (CA): Wadsworth Publishing; 1995.Mizuchi A, Miyachi Y, Tamaki K, Kukita A.cutaneous absorption of betamethasonebenzoate measured by radioimmunoassay.

vest Dermatol 1976;67:279-82.

20. Turpeinen M. Absorption of hydrocortisonefrom the skin reservoir in atopic dermatitis. Br JDermatol 1991;124:358-60.21. Gitau R, Cameron A, Fisk NM, Glover V.Fetal exposure to maternal cortisol. Lancet1998;352:707-8.22. Sirianni R, Rehman KS, Carr BR, ParkerCR Jr, Rainey WE. Corticotropin-releasinghormone directly stimulates cortisol and thecortisol biosynthetic pathway in human fetaladrenal cells. J Clin Endocrinol Metab2005;90:279-85.23. WeinstockM. The potential influence of ma-ternal stress hormones on development and

mental health of the offspring. Brain BehavImmun 2005;19:296-308.24. Eishi Y, Hirokawa K, Hatakeyama S. Long-lasting impairment of immune and endocrinesystems of offspring induced by injection ofdexamethasone into pregnant mice. Clin Immu-nol Immunopathol 1983;26:335-49.25. Ajayi GO, Fadiran EO. The effect of combinediron therapy (chemiron) and single iron therapy onthe dexamethasone-estriol reaction test for pla-centa insufficiency during normal pregnancy. ClinExp Obstet Gynecol 1999;26:27-30.26. Lipworth BJ. Systemic adverse effects ofinhaled corticosteroid therapy: a systematic re-

view and meta-analysis. Arch Intern Med1999;159:941-55.27. Negulescu RI, Strecker JR, Lauritzen C, PalS. The influence of betamethasone on the feto-placental unit: a preliminary report. J PerinatMed 1977;5:120-32.28. Jackson LD, Polygenis D, McIvor RA,Worthington I. Comparative efficacy and safetyof inhaled corticosteroids in asthma. Can J ClinPharmacol 1999;6:26-37.29. Salomon DS, Pratt RM. Involvement ofglucocorticoids in the development of thesecondary palate. Differentiation 1979;13:141-54.

www.AJOG.org Obstetrics ResearchDECEMBER 2007 American Journal of Obstetrics & Gynecology 585.e7

Maternal corticosteroid use and orofacial cleftsMATERIALS AND METHODSRESULTSCOMMENTACKNOWLEDGMENTREFERENCES