maternal coffee consumption during pregnancy and risk of ... · 9/18/2013 · between maternal...

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Maternal coffee consumption during pregnancy and riskof childhood acute leukemia: a metaanalysisJian Cheng, BMSc; Hong Su, PhD; Rui Zhu, BMSc; Xu Wang, BMSc; Meiling Peng, MD;Jian Song, BMSc; Dongdong Fan, MD

OBJECTIVE: This study was undertaken to explore the association drinkers, and 1.72 (95% CI, 1.37e2.16) for high-level drinkers.
between maternal coffee consumption during pregnancy and child-hood acute leukemia (AL).
STUDY DESIGN: The PubMed database was used to search studiesup to May 5, 2013, and the lists of references of retrieved articleswere also screened to identify additional relevant studies. Studieswere included if they reported the odds ratio and corresponding95% confidence interval (CI) of childhood AL, including childhoodacute lymphoblastic leukemia (ALL) and acute myeloid leukemia(AML), with respect to maternal coffee consumption duringpregnancy.

RESULTS: Compared with non/lowest drinkers, the combined oddsratio regarding the relationship of maternal coffee consumption duringpregnancy and childhood AL was 1.22 (95% CI, 1.04e1.43) for everdrinkers, 1.16 (95% CI, 1.00e1.34) for low to moderate-level

From the Departments of Epidemiology andHealth Statistics (Mr Cheng, Dr Su, Mr Wang,Dr Peng, Mr Song, and Dr Fan) and Child andHealth Care (Ms Zhu), School of Public Health,Anhui Medical University, Hefei, Anhui, China.

Received June 22, 2013; revised Aug. 16, 2013;accepted Sept. 18, 2013.

The authors report no conflict of interest.

Reprints: Hong Su, PhD, Department ofEpidemiology and Health Statistics, School ofPublic Health, Anhui Medical University, 81Meishan Rd., Hefei, Anhui Province 230032,China. [email protected].

0002-9378/$36.00ª 2014 Mosby, Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2013.09.026

When analysis was conducted by subtypes of childhood AL, maternalcoffee consumption (high-level drinkers vs non/lowest drinkers) wasstatistically significantly associated with childhood ALL (1.65; 95% CI,1.28e2.12) and childhood AML (1.58; 95% CI, 1.20e2.08). Weobserved the linear dose-response relationship of coffee consumptionand childhood AL (P for nonlinearity ¼ .68), including childhood ALLand childhood AML; with increased coffee consumption, the risk ofchildhood AL increased.

CONCLUSION: The findings of the metaanalysis suggest that maternalcoffee consumption during pregnancy may increase the risk ofchildhood AL. Because of limited studies, further prospective studiesare urgently needed to explore the adverse effect of coffee con-sumption on childhood AL.

Key words: childhood leukemia, coffee consumption, metaanalysis

Cite this article as: Cheng J, Su H, Zhu R, et al. Maternal coffee consumption during pregnancy and risk of childhood acute leukemia: a metaanalysis. Am J ObstetGynecol 2014;210:151.e1-10.

hildhood cancer has been a major
C global health issue. Each year,nearly 100,000 children age <15 yearsdie of cancer,>90% of them in resource-limited countries.1 Acute leukemia (AL)is one of the most common childhoodcancers, and morbidity has been in-creasing in Europe and the United Statesin past decades.2-4 Among AL, acute
lymphoblastic leukemia (ALL) was themost common subtype, followed by acutemyeloid leukemia (AML), also calledacute nonlymphoblastic leukemia.5

Despite decades of research, the causeof childhood AL remained unclear withthe exception of radiation exposure anda few chromosomal and genetic abnor-malities. The attention of recent researchon finding risk factors of childhood ALhas been focused on parental environ-mental exposures during pregnancy.Factors such as maternal alcohol con-sumption and smoking during pregnancyhave been extensively explored. Accord-ing to 2 recent metaanalyses, positive as-sociation was found between childhoodleukemia and maternal alcohol duringpregnancy,6 but not maternal smoking.7

Among environmental exposures, theimpact of maternal coffee consumptionduring pregnancy on childhood AL wasanother research hotspot. Coffee, one ofthe most widely consumed beverages inthe world, contains caffeine, which mayresult in childhood AL. For instance,

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caffeinemay act as a topoisomerase (topo)II inhibitor,8 a DNA repair inhibitor ora carcinogen metabolism inhibitor.9 Itinduces chromosomal aberrations andtranslocations, such as abnormalities ofchromosome 11q23, which was taken as acause for the pathogenesis of infant leu-kemia.8 However, the results based onepidemiological studies on the associa-tion between coffee consumption duringpregnancy with childhood AL were in-consistent. Although the risk estimatesconcerning the association of maternalcoffee consumptionduring pregnancy andchildhood ALL from previous publishedstudieswerepooledbyMilne et al10 in theiroriginal paper, but only 2 publishedstudies were included and the impact ofcoffee consumption during pregnancyon childhood AL and childhood AMLremains unknown. Therefore, we aimedto conduct a comprehensive metaanalysisof identified studies to evaluate the rela-tionship of maternal coffee consumptionduring pregnancy and childhood AL andits subtypes (ALL, AML).

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FIGURE 1Process of study selection

Cheng. Maternal coffee consumption and risk of childhood leukemia. Am J Obstet Gynecol 2014.

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MATERIALS AND METHODS

Search strategyThe PubMed database was searched forstudies up to May 5, 2013, with thefollowing key words: “coffee,” “caffeine,”“beverage,” “leukemia,” and “AL.” Allsubterms were included and no languagerestrictions were imposed. In addition,the lists of references in previous studies(including reviews) were also screened toidentify additional relevant studies.

Study selectionWe included the identified studies thatmeet the following criteria: (1) case-control or cohort study design; (2) mainexposure of interest was coffee con-sumption during pregnancy; (3) out-come of interest was childhood AL, ALL,or AML (or acute nonlymphoblasticleukemia); (4) targeted population waschildren<18 years; and (5) they providedthe odds ratio (OR) and corresponding

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95% confidence interval (CI) (or dataallowed to recalculate them).

Data extractionData from identified studies were ex-tracted independently by 2 investigatorsusing a standardized data collectionform, and then compared. For eachincluded study, the data extractedwere the following: first author’s lastname, year of publication, location,study period, children’s age range, thenumber of cases and controls, type ofleukemia, level of coffee consumptionduring pregnancy, effect estimates (ORand 95% CI), adjustment for potentialconfounding factors, and assessmentmethods of coffee consumption (inter-view or self-administrated).

Statistical analysisWe extracted study-specific risk estimatesand calculated the summary estimates by

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combining log risk estimates weighted bythe inverse of their variances. First, wecompared the risk of childhood AL inever drinkers with never/lowest drinkers.Several studies did not provide the risk ofchildhood AL for ever drinkers. For thosestudies, a summary ORwas calculated forever drinkers using the reported risk es-timates for each coffee consumption level.Then the summary OR was used in finalmetaanalysis when pooling the overallrisk of childhood AL for ever drinkers.

Second, to estimate the summary ORfor various levels of coffee consumptionduring pregnancy, we also calculatedthe study-specific estimates for low tomoderate coffee consumption (definedas >0 to �3 cups/d for Menegauxet al5,11; >0 to �1 cup/d and >1 to�2 cups/d for Bonaventure et al12;>0 to <3 cups/d for Clavel et al4; >0to <2 cups/d for Milne et al10; >0 to<3 times/wk for Ross et al8) and for highcoffee consumption (defined as >4 to�8 cups/d and �8 cups/d for Menegauxet al5; >3 cups/d for Menegaux et al11;>2 cups/d for Bonaventure et al12;�3 forMenegaux et al11; �2 cups/d for Milneet al10; �4 times/wk for Ross et al8).Statistical heterogeneity between studieswas evaluated with Cochran Q and I2

statistics with corresponding P valueand P < .1 was considered statisticallysignificant. Fixed effect model wasused to calculate the pooled OR if noheterogeneity was observed, otherwise,random effect model was used.

Since different levels of coffee con-sumption were analyzed in differentstudies, we also conducted a dose-response metaanalysis to explore thepooled dose-response relationship be-tween coffee consumption during preg-nancy and childhoodAL. Studies includedin final dose-response had to meet thefollowing criteria: (1) at least 3 levels ofcoffee consumption, including the refer-ence levelwere presented; and (2) numberof cases and controls, and OR (for case-control study) with corresponding 95%CI for each level of coffee consumptionwere reported.Themedianormean coffeeconsumption for each level was assignedto each corresponding OR for each study.The midpoint of the upper and lowerboundaries in each level was assigned as

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TABLE 1Characteristics of studies included in metaanalysis

ReferenceCountry andstudy; period Age range Cases/controls Type of leukemia (no.) Coffee consumption

Effect estimation (95% CI)

AdjustmentsAL ALL AML (ANLL)

Ross et al,8

1996aUnited States andCanada; NA

<12.5 mo 84/97 AL (84)ALL (54)AML (30)

Never�3 times/wk�4 times/wk

Reference1.5 (0.7e3.3)2.5 (1.0e6.2)

Reference1.1 (0.4e3.0)2.3 (0.7e8.2)

Reference2.4 (0.6e9.2)2.6 (0.7e10.0)

Socioeconomicstatus, maternaleducation

Petridou et al,15

1997aGreece; 1993through 1994

0e14 y 153/300 AL (153) NeverEver

Reference0.89 (0.55e1.46)

Gender, age,place of residence

Clavel et al,4

2004aFrance; 1995through 1999

<15 y 219/105 AL (219) NeverEver�3 cups/d>3 cups/d

Reference1.8 (1.0e3.3)1.6 (0.9e2.9)4.1 (1.6e10.1)

Gender, age,ethnic origin,hospital,socioeconomicstatus, maternaleducation

Menegauxet al,5 2005a

France; 1995through 1999

<15 y 280/288 AL (280)ALL (240)ANLL (40)

Never�3 cups/d4-8 cups/d>8 cups/d

Reference1.1 (0.7e1.8)2.4 (1.3e4.7)3.1 (1.0e9.5)

Reference1.6 (0.6e4.3)2.8 (0.7e10.4)3.0 (0.3e35.1)

Gender, age,ethnic origin,socioeconomicstatus

Menegauxet al,11 2007b


<15 y 472/567 AL (472)ALL (407)AML (62)

NeverEver�3 cups/d>3 cups/d

Reference1.1 (0.9e1.5)1.1 (0.8e1.4)1.5 (0.9e2.4)

Reference1.1 (0.8e1.4)1.1 (0.8e1.4)1.5 (0.9e2.4)

Reference1.6 (0.8e2.9)1.6 (0.8e3.0)1.4 (0.5e4.4)

Gender, age,region,socioprofessionalcategory, andbirth order

Milne et al,10

2011bAustralia; 2003through 2006

�14 y 337/697 ALL (337) NeverEver<2 cups/d�2 cups/d

Reference0.89 (0.61e1.30)0.77 (0.51e1.16)1.12 (0.72e1.74)

Age, sex, state ofresidence, andmaternaleducation

Bonaventureet al,12 2013a


�14 y 764/1681 AL (764)ALL (648)AML (101)

Never/occasional<1 cup/d1-2 cups/d>2 cups/d

Reference1.0 (0.8e1.3)1.3 (1.0e1.7)1.6 (1.2e2.1)

Reference1.3 (0.7e2.1)1.8 (1.0e3.3)2.4 (1.3e4.3)

Reference1.0 (0.8e1.3)1.3 (1.0e1.7)1.5 (1.1e2.0)

Gender, age,maternaleducation, andsocioeconomicstatus

AL, acute leukemia; ALL, acute lymphoblastic leukemia; AML, acute myelocytic leukemia; ANLL, acute nonlymphocytic leukemia; CI, confidence interval; NA, no records.

a Studies used interview for coffee assessment; b Studies used self-administered questionnaire for coffee assessment.


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FIGURE 2Summary ORs of childhood acute leukemia for ever, low tomoderate-level, and high-level drinkers vs never/lowest drinkers

Squares indicate study-specific risk estimates; diamond indicates summary OR with corresponding

95% confidence interval (CI).

OR, odds ratio.



the average intake if the median or meancoffee consumption for each level was notprovided. If the upper boundary of thehighest level was not provided, weassumed that the boundary had the sameamplitude as the adjacent category.

To examine the nonlinear relation-ship between coffee consumption duringpregnancy and childhood AL, a 2-stagerandom effects dose-response meta-analysis was performed, taking into ac-count the heterogeneity among studiesrecently proposed by Orsini et al.13

Briefly, for each identified study con-tributing to this metaanalysis, the log ORwas calculated for various levels of coffeeconsumption. Then a restricted cubicspline model, with 4 knots at percentiles(5%; 35%; 65%; 95%) of levels of coffeeconsumption, was estimated using gen-eralized least square regression, takinginto account the correlation within each


set of published ORs. The study-specificestimates were combined using fixedeffects restricted cubic spline modelswith 4 knots and using the method ofGreenland and Longnecker14 to estimatethe covariances of OR. If P < .05, thenonlinearity dose-response relationshipwas considered to exist.We conducted stratified analysis by

the subtype of childhood AL andinvestigated the following potentialsources of heterogeneity: assessmentmethods of coffee consumption andstudy population. Meanwhile, publica-tion bias was also assessed by con-structing funnel plots and by Eggerregression asymmetry test. P < .05 wasconsidered representative of statisticallysignificant publication bias. All sta-tistical analyses were conducted usingsoftware (Stata, version 11; StataCorp,College Station, TX).

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RESULTS

A total of 7 published studies (Figure 1)regarding the relationship between cof-fee consumption during pregnancy andchildhood AL were included in ourmetaanalysis. All the studies were case-control design (Table 1), of which 4were conducted in France, 1 in Australia,1 in Greece, and 1 in North America.Among these studies, 5 used self-administrated questionnaires for coffeeconsumption assessment, and the othersused interview technology for coffeeconsumption assessment. Five evaluatedthe association between coffee consu-mption during pregnancy and child-hood AL,4,8,11,12,15 5 assessed childhoodALL,5,8,10-12 and 4 evaluated childhoodAML.5,8,11,12

Maternal coffee consumption duringpregnancy on childhood ALRisk estimates for childhood AL areshown in Figure 2. Comparedwith never/lowest drinkers, adverse effect ofmaternalcoffee consumption during pregnancy onchildhood AL was observed in everdrinkers (1.22; 95% CI, 1.04e1.43), lowtomoderate-level drinkers (1.16; 95%CI,1.00e1.34), and high-level drinkers(1.72; 95% CI, 1.37e2.16). There wasno statistically significant heterogeneityamong studies (I2¼ 32.3%,P¼ .206; I2¼0.0%, P ¼ .615; I2 ¼ 35.0%, P ¼ .202).Regarding the assessment of publicationbias, neither Begg bias (Figure 3) norEgger bias was observed (P ¼ .406).

Maternal coffee consumption duringpregnancy on childhood ALLFigure 4 presents the summary ORs forchildhood ALL. Compared with thenever/lowest drinkers, the summary ORwas 1.26 (95% CI, 1.05e1.50) for everdrinkers, 1.09 (95% CI, 0.91e1.31) forlow to moderate-level drinkers, and1.65 (95% CI, 1.28e2.12) for high-leveldrinkers. Significant between-study het-erogeneity was not noted in last 2 (I2 ¼24.1%, P ¼ .261; I2 ¼ 47.0%, P ¼ .110).When the results on ever drinkers werepooled in random effect model, theadverse effect of ever drinkers was notobserved: 1.30 (95%CI, 0.97e1.73).With

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FIGURE 3Begg funnel plot with 95% confidence interval

No publication bias was noted from both visualization of funnel plot and Egger test (P ¼ .406).


FIGURE 4Summary ORs of childhood acute lymphoblastic leukemia for ever, low tomoderate-level, and high-level drinkers vs never/lowest drinkers



OR, odds ratio.


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respect to publication bias, no bias wasobserved (Egger test, P ¼ .596).

Maternal coffee consumption duringpregnancy on childhood AMLThe summary ORs for childhood AMLare presented in Figure 5. The significantassociation between childhood AML andcoffee consumption during pregnancywas observed for ever drinkers (1.35; 95%CI, 1.10e1.66) and high-level drinkers(1.58; 95% CI, 1.20e2.08), but not forlow to moderate-level drinkers (1.18;95% CI, 1.00e1.40). No heterogeneitywas observed (I2¼ 17.0%, P¼ .306; I2¼0.0%, P ¼ .643; I2 ¼ 0.0%, P ¼ .486).There was publication bias among studiesincluded in this metaanalysis (Egger test,P ¼ .018).

Dose-response relationshipSix studies were included in final dose-response metaanalysis with one8 removeddue to no available data presented for casesand controls. Among these studies, 3,4,11,12

4,5,10-12 and 35,11,12 were used to explorethe dose-response relationship betweencoffee consumptionduring pregnancy andchildhood AL, childhood ALL, and child-hood AML, respectively.

For childhood AL, the nonlinearlyrelationship was not observed regard-ing maternal coffee consumption withchildhood AL (P for nonlinearity ¼ .68)(Figure 6, A). Compared with never/lowest drinkers, the pooledORswere 1.10(95% CI, 0.94e1.29) for 1 cup/d, 1.24(95% CI, 1.06e1.46) for 1-2 cups/d,1.53(95%CI,1.21e1.93) for2-3cups/d, and1.96 (95% CI, 1.32e2.92) for 4-5 cups/d.

The nonlinearly relationships ofmaternal coffee consumption duringpregnancy with childhood ALLwere alsonot noted (P for nonlinearity ¼ .67)(Figure 6, B), and the summary ORswere 1.00 (95% CI, 0.89e1.14) for 0-1cup/d, 1.04 (95% CI, 0.86e1.25) for1 cup/d, 1.10 (95%CI, 0.91e1.34) for 1-2cups/d, 1.30 (95% CI, 1.05e1.60) for 2-3cups/d, 1.41 (95% CI, 1.11e1.78) for3 cups/d, 1.74 (95% CI, 1.29e2.35) for4-5 cups/d, 2.08 (95% CI, 1.46e2.94)for 6 cups/d, and 3.02 (95% CI,1.17e7.78) for 10 cups/d.

We found linear association be-tween maternal coffee consumption and


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FIGURE 5Summary ORs of childhood acute myeloid leukemia for ever, low tomoderate-level, and high-level drinkers vs never/lowest drinkers





childhood AML (P for nonlinearity ¼.65) (Figure 6, C). The risk of childhoodAML for coffee consumption was 1.10(95% CI, 0.96e1.25), 1.15 (95% CI,0.98e1.34), 1.24 (95% CI, 1.04e1.47),1.39 (95% CI, 1.10e1.75), 1.48 (95%CI, 1.18e1.84), and 1.65 (95% CI,1.26e2.16) for 1, 1-2, 2-3, 4-5, 6, and10 cups/d, respectively.

Subgroup and sensitivity analysisThe studies were stratified by studypopulation and assessment methods ofcoffee consumption for ever drinkers(Table 2). In the subgroup analysis bystudy population, we noted that coffeeconsumption during pregnancy wassignificantly associated with increasedrisk of childhood ALL (OR, 1.45; 95%CI, 1.01e2.07) and childhood AML(OR, 1.31; 95% CI, 1.07e1.62) amongEuropeans, while no such associationwas observed among people in other


countries. When stratified by assessmentmethods of coffee consumption, theadverse effects of coffee consumption forever drinkers on childhood AL (OR,1.72; 95% CI, 1.30e2.28) and childhoodAML (OR, 1.33; 95%CI, 1.07e1.65) wereobserved for studies using interviewingtechniques, but not among studies usingself-administrated questionnaire. Theheterogeneity was only observed (P¼ .08,I2 ¼ 60.9%) when assessing the associa-tion between coffee consumption andchildhood ALL among Europeans. Whenwe conducted the analysis for low tomoderate-level drinkers and high-leveldrinkers, the pooled effect estimateswere similar with that for ever drinkers,and no heterogeneity was noted in allresults (data not shown).Because limited cases of AL (84) were

analyzed by Ross et al,8 the study wasremoved to observe the stability of theresults. For high-level drinkers, the

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positive relationships with childhood AL(OR, 1.68; 95% CI, 1.33e2.12), ALL(OR, 1.71; 95% CI, 1.14e2.55), andAML (OR, 1.55; 95% CI, 1.17e2.05)remained statistically significant. Forever drinkers, the adverse effect of coffeeconsumption during pregnancy onchildhood AMLwas observed (OR, 1.32;95% CI, 1.07e1.62), but not on child-hood AL and ALL. However, for low tomoderate-level drinkers, the positiverelationships with childhood AL, ALL,and AML were not noted.

COMMENT

The current metaanalysis evaluated thepotential association between maternalcoffee consumption during pregnancyand childhood AL based on 7 case-control studies, with a pooled total of2090 cases and 3630 controls. The resultsindicated that maternal coffee con-sumption during pregnancy was signifi-cantly associated with childhood AL.Overall, compared with never/lowestdrinkers, the risk of childhood ALincreased by 22% for ever drinkers and72% for high-level drinkers. In addition,the statistically significant relationshipsbetween maternal coffee consumptionduring pregnancy and childhood ALLand childhood AML were also noted,especially for high-level drinkers withsummaryORs ranging from 1.58 to 1.65.

There are some potential mechanismsthrough which coffee consumption mayincrease the risk of childhood AL. Coffeecontains a large amount of caffeine,which is considered a topo II inhibitor.8

According to previous studies, DNAtopo II, an important enzyme in the un-winding and regulation of DNA, isnecessary for gene transcription, DNArecombination, and replication.16 Sincethe proliferation of cells during fetaldevelopment and topo II levels is greatestin rapidly dividing cells,17 excessiveexposure to topo II inhibitors, such ascoffee, during pregnancy may lead todevelopmental abnormalities in the fetus.For instance, it is generally believed thatDNA topo II inhibitors can cause illegit-imate recombination or translocationpreferentially at the 11q23 site,18 resem-bling that induced by epipodophyllotox-ins,19 as has commonly been observed in

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FIGURE 6Dose-response relationships between maternal coffee consumption andrisk of childhood

)


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infants with leukemia20 and postulated asa factor in the pathogenesis of the dis-ease.8 Previous studies have shown thatcaffeine has the capacity of inhibitingsome genes, such as the tumor suppressorgene (P53)21 and ataxia telangiectasiamutated gene,22 which were associatedwith childhood AL.23,24

Furthermore, the interaction of coffeeconsumption and maternal lifestyleduring pregnancy on childhood AL hasbeen reported. Milne et al10 has assessedthe interaction of coffee consumptionandmaternal smoking during pregnancyin the development of childhood ALthrough pooling results with prior pub-lished studies. They found that smokingstatus might modify the association be-tween coffee consumption and child-hood ALL and the summary OR (2.32;95% CI, 1.51e3.57) increased for >3cups/d of coffee during pregnancyamong nonsmokers, while that amongsmoking mothers was 1.01 (95% CI,0.77e1.33). Later, Bonaventure et al12

also explored the potential effect ofmaternal smoking status during preg-nancy on the association between coffeeconsumption and childhood AL as wellas its subtypes. They observed that forchildren born to nonsmoking mothers,the OR was 1.7 (95% CI, 1.3e2.3) [ALL1.5 (95% CI, 1.1e2.1) and AML 3.2(95% CI, 1.6e6.2); and for childrenborn to smoking mothers: AL 1.2 (95%CI, 0.7e2.0); ALL 1.2 (95% CI,0.7e2.1); and AML 1.6 (95% CI,0.4e6.6)]. It has been shown that, for agiven caffeine intake, blood caffeineconcentrations were lower in smoking

A, Acute leukemia (AL) (P for nonlinearity ¼.68); B, acute lymphoblastic leukemia (ALL

(P for nonlinearity ¼ .67); and C, acute

myeloid leukemia (AML) (P for nonlinearity ¼.65). Data were modeled with fixed effects

restricted cubic spline models with 4 knots

(5%; 35%; 65%; 95%) and using Greenland

and Longnecker14 method to estimate co-

variances of odds ratio (OR). Solid line and long

dash line represented estimated OR and its

95% confidence interval. Short dash line

represented linear relationship.

Cheng. Maternal coffee consumption and risk of childhoodleukemia. Am J Obstet Gynecol 2014.


)

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TABLE 2Stratified analysis by study population and coffee assessment for ever drinkers vs non/lowest drinkers

Variables Study, n Case, n

OR (95% CI) Heterogeneity test

ALL AML ALL AML

Study population

Europe 5 1669 1.45 (1.01e2.07)a 1.31(1.07e1.62) P ¼ .08, I2 ¼ 60.9% P ¼ .38, I2 ¼ 0.0%

Others 2 421 0.98 (0.70e1.38) 2.5 (0.97e6.48) P ¼ .25, I2 ¼ 24.5% P ¼ .93, I2 ¼ 0.0%

Coffee assessment

Interview 5 1281 1.72 (1.30e2.28) 1.33 (1.07e1.65) P ¼ .92, I2 ¼ 0.0% P ¼ .19, I2 ¼ 39.9%

Questionnaire 2 809 1.02 (0.82e1.28) 1.60 (0.80e2.90) P ¼ .89, I2 ¼ 0.18%

ALL, acute lymphocytic leukemia; AML, acute myelocytic leukemia; CI, confidence interval; OR, odds ratio.

a Random effect model.



than in nonsmoking women.25 The dif-ferent observation may be explained bythe known accelerating effect of tobaccosmoking on caffeine metabolism26 anddecreasing the exposure to caffeine.

Because of the wide array of mea-surement categories of coffee consump-tion reported among studies, we alsoconducted dose-response analysis ofcoffee consumption during pregnancyon risk of childhood AL. In the presentmetaanalysis, we noted the linearityassociation between childhood AL (in-cluding its subtypes) and coffee con-sumption during pregnancy. Althoughthe threshold of coffee consumptionwas not identified in prior studies, whichmay due to the variation of ethnicity orcoffee consumption category existingin pregnant women over the world, weobserved the significant associationbetween pregnant women who drank1-2 cups/d of coffee and childhoodAL. The similar adverse effects onchildhood ALL and childhood AMLwere also noted for those who drank2-3 cups/d of coffee. The results showedthat with the coffee consumptionincreased, the risk of childhood AL andits subtypes elevated, which were similarwith previous studies. Bonaventureet al12 has reported that OR of coffeeconsumption increased linearly withdaily intake (P for trend .001). In apopulation-based study, Ross et al8

has shown that there was a statisti-cally significant positive association


(P for trend ¼ .04) between childhoodAML and the increasing consumptionof DNA topo II inhibitors containedin foods. Thus, we speculated that forthose born to nonsmoking mothers,coffee consumption might aggravatethe accumulation of caffeine in thebody and lead to a greater risk of child-hood AL.We also conducted a subgroup anal-

ysis by study population and coffeeassessment for ever drinkers vs never/lowest drinkers. The pooled effect esti-mates indicated that the significantrelationship of coffee consumption andchildhood AL existed only in Europe,not in other countries. The differenceobserved may be explained, at least inpart, by the variations of coffee con-sumption among people in Europe andother countries. Although the UnitedStates was one of the countries withthe highest coffee consumption, only 1study8 was included in our metaanalysisand limited numbers of cases (84) wereanalyzed, therefore, it might be insuffi-cient to detect the risk of childhood AL.In addition, a possible role of ethnicdifferences in genetic backgrounds, thedifferences of environment they lived in,and potential lifestyles should also betaken into account. When the subgroupanalysis was performed by assessmentmethods of coffee consumption, wenoted the positive association betweencoffee consumption and childhood ALLand childhood AML among studies

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using interviewing techniques, but notamong studies using self-administratedquestionnaire. The contrast may due toa consequence of information bias(mainly recall bias) because of differentassessment techniques used in differentstudies.

Ross et al8 reported no risk of child-hood AL and childhood AML fordecaffeinated coffee drinkers, but only64 and 43 cases were included, respec-tively. Due to limited studies thatexamined the risk of decaffeinated coffeeintake during pregnancy in relation tochildhood AL, there were no availabledata for us to conduct a metaanalysis ofdecaffeinated coffee intake. Regardingthe detailed sensitivity period duringpregnancy, in which the risk of child-hood AL for coffee drinkers may begreater, Ross et al8 has proposed that a9-month window was extremely impor-tant for epidemiologic studies. Butfew studies have explored it. Milne et al10

has explored whether maternal coffeeconsumption during the last 6 monthsof pregnancy was associated with child-hood ALL. But no association wasfound for drinkers (ever, <2 cups and>2 cups/d).

The strengths of this metaanalysis wasthat we have a systematic and quantitativeassessment on the association betweenmaternal coffee consumption duringpregnancy and childhood AL (includingits subtypes), and explore the poten-tial dose-response relationship between

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them. In addition, after removing thestudies including the maximum8 andminimum sample size,12 the positive as-sociation ofmaternal coffee consumptionand childhood leukemia still remainedstatistically significant. Subgroup analysesalso confirmed the robustness of thepooled results.

Several limitations should also betaken into account when interpreting theresults in current metaanalysis. First, asall the identified studies were case-control design, history of coffee con-sumption level was wholly based onself-report. The information bias mayhave appeared in studies using self-administered questionnaires. And thesimilar interviewing technology usedin studies for case and control mothersreduced potential differential mis-classifications. However, the recall biascould not be ruled out although therewas no general awareness of a potentialrelationship between coffee consump-tion and childhood AL. Second,although most studies have adjusted formajor potential confounders, such asgender, age, maternal education, andsocioeconomic status, a metaanalysiswas unable to remove potential con-founding factors, such as alcohol con-sumption, which could be inherentin the included studies. Third, coffeeexposure was mostly assessed withrespect to the number of cups of coffeeconsumption daily. However, methodsof coffee preparation (eg, filtered,boiled) and cup size may vary consider-ably. Our results were likely be affectedby the misclassification of coffee con-sumption. Fourth, the risk of othersources of caffeine, such as cola, whichmay be associated with childhood AL,was not analyzed. Finally, only limitedpublished studies were included and themethod of control selection varied withstudies. For instance, the controls wereselected from the whole population byMenegaux et al,11 while Clavel et al4

selected the controls from the hospital.Publication bias may have occurredalthough only a publication bias wasobserved in the present study.

In summary, the results of this meta-analysis provided evidence that maternal

coffee consumption during pregnancymay be associated with increased riskof childhood AL and its subtypes.Meanwhile, the linear dose-response re-lationships between coffee consumptionduring pregnancy and childhood ALLand childhood AML were also observed,with the increasing of coffee consumptionand the risk of childhood ALL andchildhood AML increased accordingly. Inlight of limited studies included in thismetaanalysis, more prospective cohortstudies with larger sample size, well-controlled confounding factors, andmore accurate assessment of coffee con-sumption should be conducted to assesswhether this association was causal. -

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