Herbal antiemetics laxatives and in pregnancy Reproductive Toxicology

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ContentslistsavailableatScienceDirect

Reproductive Toxicology

jo u r n al hom e p ag e :w w w . e l s e v i e r . c o m / l o c a t e / r e p r o t o x

Herbal laxatives and antiemetics in pregnancy

Reza Samavati, Eszter Ducza, Judit Hajagos-Tóth, Robert Gaspar

^∗

DepartmentofPharmacodynamicsandBiopharmacy,UniversityofSzeged,Hungary

a r t i c l e i n f o

Articlehistory:

Received1February2017

Receivedinrevisedform24May2017 Accepted5June2017

Availableonline10June2017

Keywords:

Pregnancy Laxatives Antiemetic Herbal Safety

a b s t r a c t

Constipationappearsinthe2ndand3rdtrimesterofpregnancy,whilenauseaisthestrongestinthe1st trimester.Thisreviewsummarizestheapplicabilityofherballaxativesandantiemeticsinpregnancy.

Ahumanstudyhasshownthatﬂaxoilaslaxativeissafefrom2ndtrimester.Humandataisnot availableabouttherhubarb,butanimalstudiesrevealthatitsemodincontentinducesfetalabnormalities.

Fenugreekinducesteratogenicmalformationbothinhumanandanimals.Sennaseedisprovedasasafe laxativeinpregnancy.Theantiemeticgingerissafeduring1sttrimester,butitreducesthegestational periodwhenappliedfromthe2ndtrimester.Cannabisinducesfetalneurologicaldisorderswhilefennel canshortenthegestationalage.

Thereisherbalalternativeforlaxativetherapy(senna)forthewholelengthofpregnancy,butnausea andvomitingmightbereducedbyherbalmedicine(ginger)safelyinthe1sttrimester,only.

1. Introduction

Severalmaternalsymptomsmaycausedifﬁcultiesduringpreg- nancy.Evenmilderdisordersmaychallengethetherapybecause oftheriskofteratogenicorembryotoxicconsequences.ADutch population-basedcohortstudyfoundthat5%ofpregnantwomen receive potentiallyteratogenic drugsduring pregnancy [1].The majorityofpregnantwomentrytoavoidpharmacotherapy,and havebetterconﬁdencetowardsalternativetherapies,especiallyin thelasttrimesterofpregnancy.Accordingtoasurvey,themost commonalternativeremediesaretheoralherbalproductsamong womeninthethirdtrimester[2],althoughtheirsafetyisnotalways proved.Additionally,therearethedifferentkindsoforientalherbal shops among the majorsources of herbal products, where the advertisementsandtheprovidedinformationdonotalwayscom- plywiththeregulations[3].

Constipation,nauseaandvomitingareamongthemostfrequent complaintsinpregnancy.

Constipationmainlyappearsinthesecondandthirdtrimester, itsprevalenceisaround40%duringpregnancy[4].Themostcom- monconsequencesoflongtermconstipationarehemorrhoidsand analﬁssures[5].Severalfactorscanbementionedaspotentialrea- sonsforthesymptom:slowergastrointestinal(GI)transittime, higherplasmalevelofprogesteroneandmechanicalobstruction [6].

∗Correspondingauthorat:EotvosStreet6,SzegedH-6720,Hungary.

E-mailaddress:gaspar@pharm.u-szeged.hu(R.Gaspar).

The globalprevalence of nauseais about 70%, while vomit- ing occurs in halfof pregnancies [7]. The highplasma level of humanchorionicgonadotropinandtheincreasedplacentalmass areamongthemainfactorsthatincreasetheseverityofvomiting andmayleadtohyperemesisgravidarum.Thisconditionisone ofthemostfrequentreasonsforthehospitalizationandtheelec- trolytetherapyofpregnantwomen[8].Themajorproblemisthat nauseaandvomitingappearintheﬁrsttrimester,whenanytype ofpharmacologicalorherbaltreatmentmighthaveateratogenic riskandmaycausefearinmothers[9].

Theaimofthisreviewistosummarizetherisksofwell-known herballaxativesandantiemeticsinpregnancybypresentingpre- clinicalandclinicalevidence.

2. Searchstrategy

Asystematic literaturesearchfortoxicity ofherballaxatives andantiemeticsduringpregnancyinPubMed,GoogleScholarand Web of Knowledge wasperformed (1980–2016). Search words were “ herbal laxatives”, “herbalantiemetics”, followed by the

“toxic”,“adverseeffects”,and“gestation”, or“herbalmedicines”

combinedwith“prenatal”,“postnatal”,“duringpregnancy”,“ter- atogeniceffect”, “safety”, and “ harm”respectively. Search was limited totheEnglish language.Cohortstudies, reviews,Meta- analysesandrandomized-controlledtrialswereselected.Human studieshavebeenincludedinthereviewwhenthenumberofpar- ticipantswashigherthan600andthestudyintervalwasatleast4 years.Animalstudieshavebeenincludedwhenhumandatawere http://dx.doi.org/10.1016/j.reprotox.2017.06.041

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notavailableorfew.Thetotalnumberofidentiﬁedpapersisnot recorded,but76articleswerereviewedinthispublication.

3. Herballaxativesinpregnancy

3.1. Rhubarb(Rheumemodi)

Rhubarbcontains emodin,apurgativeresin (6-methyl-1,3,8- trihydroxyanthraquinone).Thecytotoxiceffects ofemodinwere investigatedonmouseembryosattheblastocyststage,followedby embryonicattachmentandoutgrowthinvitroandinvivoimplanta- tionbyembryotransfer[10].Afterthetreatmentofblastocystswith 25–75␮Memodin,theyobservedsigniﬁcantlyincreasedapoptosis anda correspondingdecreasein totalcellnumber. In compari- sonwiththecontrolgroup,blastocystspretreated withemodin showedasigniﬁcantlylowerimplantationsuccessrate.Further- more,invitrotreatmentwith25–75␮Memodinwasassociated with decreased fetal weight and increased resorption of post- implantation embryos. Through an in vivo mouse model, they showedthat consumptionofdrinkingwatercontaminatedwith emodincanleadtoapoptosisandreducedcellproliferation,and inhibitedearlyembryonicdevelopmentintheblastocyststage.

Inanotherinvestigation,thedevelopmentaltoxicityofemodin wasevaluated inmiceandrats[11]. Theyselectedlowdoseof 425ppm/day emodinfor ratsaccordingto(National Toxicology Program,2002a),becauseitwasnotlikelytocausematernalor fetal toxicity. In this study the middle dose was 850ppm/day and high dose of 1700ppm/day was expected to cause significant maternal toxicity when it was administrated during the embryo/fetaldevelopment,andpossiblyreducedfetalbodyweight.

DoseswereappliedthroughNIH-07groundrodentdietfromthe gestationalday6untiltheday20.Miceweretreated withlow dose600ppm/dayofemodinduetosamereasonasdescribedfor rats.Chosendosewasbasedonasignificantdecreaseinmater- nalweightgain frompregnancydays15–17duringa screening study (National Toxicology Program, 2000) at the low dose of 750ppm(115mgemodin/kg/kday).Inthiscasethemiddledose was 2500ppm/day. The selected high dose 6000ppm/day was appliedduringembryo/fetaldevelopment.Administrationroute wassimilartoratsandstarted fromthepregnancyday6 until day17.Thetreatmentsoutcomedidnotshowanymaternaldeath, butmaternalbodyweight,weightgainduringtreatment,andcor- rectedweightgainwereobservedinadecreasingpatterninthe rats.Moreover,thesesymptomsappearedmoresignificantlydur- ingtreatmentatthehighdose.Inmice,maternalbodyweightand weightgainweredecreasedatthehighdoseaswell.Otherevalu- atedparameterssuchasfetalsexratio,prenatalmortality,livelitter sizeandmorphologicaldevelopmentwereunaffectedinbothrats andmice.Ontheotherhand,theyobservedatthehighdosethat rataveragefetalbodyweightperlitterwasunaffected,whileitwas significantlyreducedinmice.

Controlledhumandataisnotavailableabouttheemodineffects duringpregnancy.Inmales,however,itinhibitsthehumansperm function[12].

3.2. Fenugreek(Trigonellafoenumgraecum)

Fenugreekiscultivatedworldwideanditisoneoftheoldest traditionalmedicinalplants.Traditionally,itisknownasacooking herbbuttheseedsarealsoknowntosettlethestomachandrelieve constipation.Toxicologicalanimalstudiesevaluatedtheacutetox- icityofthefenugreekleavesandseedsandhaveshownthatthe teratogenicdoseoffenugreekcandifferbetweenspeciesandsexes [13].

Inrattreated byfenugreekseedpowder duringtheﬁrstten daysofpregnancy(175mg/kg/day),anomalieswerereported[14]

including inverted/averted claw (18% and 21%), shoulder joint defect,tailkinking,non-ossiﬁedskullbonesandneuralpore(18%), clubbingof hind limb (9%), and enlarged neural canal (6%). In anacutetreatmentstudyduringtheorganogenesisperiod (day 10ofgestation),asingleintraperitonealdoseoffenugreekaque- ous extract (0.8, 1.6 and 3.2g/kg) increased the mortalityrate inembryosinadosedependentmanner[13].Anotherseparate studyalsoreportedthatfenugreekdecoction(0.8,1.6,and3.2g/kg), administratedintraperitoneallytorats,decreasedthefetalearto ear diameter and increasedthe fetal mortality rate[15].Addi- tionally,singleintraperitonealinjectionoffenugreekleafaqueous extract(3.2g/kg)intheday10ofthepregnancy(thetimeoforgano- genesisinitiationanddevelopmentoflimbbud)cancausesevere adversealterationsinthefetus,suchasdisorderindevelopingthe longboneofthehindlimb[16].

Studiesonmiceshowedthatlyophilizedfenugreekseedsaque- ous extract supplementation(500 and 1000mg/kg/day) during thewholegestationperioddecreasesthelittersize,increasespup mortality,reducesbodyweights(bodyweightwasmeasuredat postnataldays1,7,14,21and28),andinducesmalformations(cleft palateformationandabumponheadinnewborns),growthretar- dation,alteredneurobehavioralinthepostweaningperiod[17].

Bodyweightatbirthtimehasshown27%reductioninthecase of1000mg/kgtreatedmothersand32%inthe500mg/kgtreated groupcomparedwithcontrolpuppies.Brainweightreduced10%

inbothtreatedgroups.Similarconsequenceshavebeenprovedin rabbits:thedietscontaining30%fenugreekseedscausedasigniﬁ- cantreductioninfetaldevelopmentduetothereductionsofboth fetalandplacentalweightsandlittersizeatgestationday20[18].

Prenatalexposuretotheaqueousextract offenugreekseeds (500or1000mg/kg/day)canalsoinduceasigniﬁcantdecreasein thelocomotoractivityinbothmaleandfemalemice,suggesting thataqueousextractoffenugreekseedsinducesadepressiveeffect intheoffspring[17].

In humans, congenital malformation cases such as hydro- cephalus,anencephaly,cleftpalateandspinabiﬁdawerereported amongwomenwhoconsumedfenugreekseedsduringgestation [13].Interestingly,therearecasereportsofneonatesbeingborn withapeculiarodorfollowingmaternalconsumptionoffenugreek justbeforedelivery,whichsupportsthetransplacentalpassageof fenugreekcompoundstothefetus[13,19].

Itemergesfromthisevidencethatfetalmalformations,growth disturbanceanddisorderedfunctionmightbetheconsequences of fenugreekseeds containingan estrogenic feature agent that perturbstheendometrialliningsystemandinterfereswithfetal growth.Thereforemoreinvestigationisrequiredtoclarifythefenu- greekteratogeniccompound(s).

3.3. Flaxseed(Linumusitatissimum)

Flaxisalsoknownascommonflaxorlinseed.Itcontainsvarious dietarycomponentssuchasahighcontentofn-3fattyacids,fibers andothercompounds[20].Flaxisthemainherbalsourceofsec- oisolariresinoldiglucosidewhichisprecursorofenterolactonand entrodiol[21].Theselignanshavesimilarstructureto17␤-estradiol that couldexpressestrogenagonist or antiestrogenlike effects dependingondose,stageofdevelopmentanddurationoftreatment [22–24].Moreover,it alsocontains adetectableamountofcad- mium,whichcanactivatetheestrogenreceptor(ER).Itisrevealed thatestrogenicexposuresattheearlylifestagescanmodifysuscep- tibilitytodevelopingbreastcancer.Thematernaldietaryintakeof 5%or10%flaxseedduringpregnancyorlactation(betweenpostpar- tumdays5and25)mightaffect7,12dimethylbenz[a]anthracene (DMBA)-inducedmammarytumorigenesisintheratoffspring.Itis

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proclaimedthatbothinuteroandpostnatal5%and10%ﬂaxseed exposurescanshortenmammarytumorlatency,and10%ﬂaxseed exposureincreasedtumormultiplicity,comparedtothecontrols [25].

Additionally, in 8-week-old rats, ﬂaxseed exposure (10% in utero) increasedlobularER-␣ proteinlevels, and both inutero andpostnatalﬂaxseedexposuresdose-dependentlydecreasedER-

␤proteinlevelsintheterminalendbuds(TEBs)lobulesandducts.

ExposurestoflaxseedcannotalterthenumberofTEBsoraffectcell proliferationwithintheepithelialstructures.Intheothergroupof immatureratsthatwerefed5%defattedflaxseeddietforaweek(7 days),exposuretocadmiumthroughthedietwassix-foldhigher thanallowedforhumansbytheWorldHealthOrganization,and cadmiumsignificantlyaccumulatedintheliverandkidneysofthe rats.It remains tobedeterminedwhethertheincreased mam- marycancerinratsexposedtoflaxseedthroughamaternaldiet inuteroorlactationwascausedbycadmiumpresentinflaxseed, andwhetherthereduced mammaryER-␤contentwascausally connectedtotheincreasedrisk ofmammary canceramongthe offspring.Thepreclinicalstudyof Collinsetal.shownthat high flaxseed(upto40%)anddefattedflaxseed(upto26%)contentof themealhadnotanyapparentactiononpregnancyinrats[26].

Onlyonehumanstudyisavailableabouttheeffectofflaxseedin pregnancy.Flaxoilcapsuleweregivenbetweengestationalweeks 12and27foralmost400pregnantwomen,butnodifferencewas foundintimingofspontaneousdelivery.Thisstudysuggeststhat flaxseedoilisnotharmfulinthe2ndand3rdtrimesterofpreg- nancy,althoughfurtherinvestigationsarenecessarytogetmore evidenceforthesafetyofflaxoilconsumptionduringpregnancy [48].

3.4. Sennaseed(Cassiaoccidentalis)

Sennaoccidentalis,alsoknownassepticweed,coffeesennaand coffeeweedis apantropicaltraditional medicalplant.Theseeds areroasted,brewedandservedasteatotreathemorrhoids,gout, rheumatism,diabetes,and ithasdiureticandlaxativeeffectsas well.Itwasusedasanantidoteforseveraltypesofpoisonandasa potentabortifacient[27].

Inananimalmodel,thepossibletoxicityeffectoforalsub-acute administrationofsennaduringpregnancyhasbeeninvestigatedin femaleWistarrats[27].Theyweretreatedintheperiodoforgano- genesis duringpregnancy (pregnancydays 1–14), at doses 250 and500mg/kg.Aftereuthanasiaoftheanimals,thereproductive parameterswereevaluatedonthe20thdayofpregnancy.Nostatis- ticallysigniﬁcantdifferenceswerefoundbetweenthecontroland thetreatedgroupsinfetal,placentalandovarianweights;inthe numberofimplantationandresorptionsites;inthenumberofcor- pusluteumandinpre-andpost-implantationlossrates.However, thenumbersofdeadfetuseswereincreasedafterdosesof250and 500mg/kgofsenna.

Ingoat,itisreportedthatperinatalexposure(frompregnancy detectiononday27aftermatinguntildelivery)tosennaindifferent concentrations(1,2and4%sennaseedinthefood)cancausefetal deathandresorptionoffetusesathigherconcentration.Besides that,onedamfromthehigherdosetreatedgrouphadtissuelesions asvacuolationsinhepatocytesandkidneys;also,cardiacmuscle andskeletalnecrosiswasdetected.Itcancauselesionsinsciatic nervecellsaswell.Thereforeitissuggestedthat4%ofsennaseed inthefoodofgoatsistoxicduringpregnancy,butlowerconcen- trations(1or2%)havelesstoxicityinnatalandpost-natalbody development[28].

Ahumanretrospectivestudy(datafrom1980until1996) in Hungaryshowedthat,outof22,843caseswithcongenitalabnor- malities(CA),in506(2.2%)casesthemothersweretreatedwith senna,whileamong38,151controlnewborninfantswithoutCA,

937(2.5%)werebornfrommotherswhohadsennatreatment,and outof 834malformed controlswithDownsyndrome, 26(3.1%) caseshadmotherswiththeuseofsenna.Thesewomenusedsenna indosesbetween10mgand30mg,butmostofthemused20mg daily[29].Theydidnotﬁndahigherriskfor23differentCAgroups afterthesennatreatmentduringthesecondand/orthirdmonthof pregnancyamong260mothers(i.e.inthecriticalperiodofmost majorCAs,comparedwiththeir500matchedcontrols).Theyalso reportedthatpregnancydurationwasabitlonger(0.2week)and therateofpretermbirthwaslower(6.6%vs.9.2%)ascompared withmotherswhowerenotexposedtosenna.

Ina separateevaluationtheyrevealed,ifsevereconstipation inpregnantwomenrequireslaxativedrugtreatment,sennacan beadministeredsafelybecausetheydidnotﬁndahighrateofCA amongtheoffspringofpregnantwomenwhosesevereconstipation hadbeentreatedwithsenna[30].

4. Herbalantiemeticsinpregnancy

4.1. Marijuana(Cannabissativa)

Cannabisisthemostwidelyusedillicitdrugamongstpregnant womenwithaprevalenceofuserangingfrom3to30%invarious population.Ithasastrongantiemeticeffect;theoreticallyitmight beusedforthetreatmentofnauseaormorningsicknessduring pregnancy.However,itssafetyismorethandoubtful.Animaland humanstudieswerecarriedouttoclarifythetoxicityofcannabis inpregnancy.

Inastudy,pregnantmicewereexposed(nasal)for5mindaily tocannabis(0.2g)smokefromgestationalday5.5–17.5orﬁltered air(control).Itwasfoundthat5minofdailycannabisexposure candecreasethebirthweight,butthelittersizewasnotreduced;

interestingly,eventhenumberofmalepupsperlitterwashigher.

Additionally,theweightofwetplacentawasincreasedbutfetal toplacental weightratiowasdecreased in malefetuses, which showedasex-relatedeffect.Exposedfemalespresentedreduced maternalnetbodyweightgainattheendofgestation,despitea slightincreaseintheirdailyfoodintakecomparedtothecontrol group[31].

Anotherstudy applyingbehavioral assays, extracellular field potentialrecordingsandwhole-cellpatchclamprecordingsinves- tigated thematernalexposuretotheCB1cannabinoidreceptor agonistWIN55–212–2(WIN)inrats[32].Treatedpregnantrats showedasignificantdecreaseintherearingfrequency,totaldis- tance moved and mobility of theoffspring, but they showeda significantincreaseintherightingreflextime,thegroomingfre- quencyand immobility.Theyalsoreported asignificantimpair in neuromotor function.However, theamplitude of population spikes(PS)recordedfromthecerebellarPurkinjecelllayerofoff- springincreasedfollowingsynapticblockage.Maternalexposure alsodeeplyaffectedtheintrinsicpropertiesofPurkinjeneuronsof offspring.Thistreatmentincreasedthefiringregularity,firingfre- quency,amplitudeofafterhyperpolarization,thepeakamplitude ofactionpotentialandthefirstspikelatency,butontheotherhand itdecreasedsignificantlythetimetopeakanddurationofaction potentials,theinstantaneousfiringfrequency,therateofrebound actionpotentialandthevoltage“sag”ratio.Besidestheseanimal studies,thereareseveralotherinvestigationswhichrevealedthe teratogenicandtoxiceffectofcannabisexposureduringthepre- natalperiodinanimals[33].

Ontheotherhand,thereissomeevidencethatshowscannabis useduringpregnancyandlactationinhumanscancausevarious damagestothefetusandnewbornbabiesduringbreastfeeding.

In a cohort study, 5588 nulliparous women at 15±1 and 20±1 weeks of pregnancy were investigated [34]. Cases were

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included: 278 preeclampsia, 470 gestational hypertension, 633 small-for-gestational-age, 236spontaneous preterm births, and 143gestationaldiabetescases,whichwerecomparedseparately with4114 non-cases. Continued maternal marijuana use at 20 weeks of pregnancy was associated withspontaneous preterm births that were independent of cigarette smoking status and socioeconomicindex.Byanotherevaluation,among8138women inthecohort,680(8.4%)ofthemusedmarijuanaduringpregnancy.

Womenwhousedmarijuanawereyounger;hadinadequateprena- talcare;andusedtobacco,alcohol,andotherdrugsaswell.Medical comorbiditiesdidnotdifferbetweengroups.Itwasconcludedthat marijuanauseinpregnancymaynotbeanindependentriskfactor forpoorneonataloutcomesintermpregnancies[35].

Thereis a review focused onthecannabis-mediated maternal effects on the central nervous systemand sensitization to late-onsetchronicandneuropsychiatricdisorders[36].Theydid compare clinical and preclinical experimental studies on the effectsof fetalcannabis exposureuntil earlyadulthoodaswell.

Preclinical experimental models confirmed clinical studies and revealed that cannabis exposure canevoke significant molecu- larmodificationstoneurodevelopmentalprograms,whichleadto neurophysiologicalandbehavioralabnormalities.Therearemore documentsthatconfirmcannabiscancausesignificantneurobi- ologicalandneuropsychiatricconsequences onthehumanfetus [37].Analyzing ofthebirth outcomesdatafrom24874 women withcannabisuseinacohortstudyduring7years(2000–2006) attheMaterMothers’HospitalinBrisbane/Australia,shownlow birthweight(oddsratio(OR)=1.7;95%confidenceinterval(CI):

1.3–2.2), preterm labor (OR=1.5; 95% CI: 1.1–1.9), small for gestational age (OR=2.2; 95% CI: 1.8–2.7), and more frequent admissiontotheneonatalintensivecareunit (OR=2.0;95%CI:

1.7–2.4)[38].Similaradversebirthoutcomes(lowbirthweight) werereportedafterthematernalcannabisuseduringpregnancy [39].

4.2. Fennel(Foeniculumvulgare)

Theeffects of fennel essential oil(FEO) on theuterinecon- traction and evaluation of lethal dose 50% (LD50) in rat were studied[40].Itwasfoundthataftertheadministrationofdiffer- entdosesofFEO(10,20,25,40and50␮g/ml),theoxytocin(0.1, 1and10mU/ml)–andprostaglandinE2(5×10⁻⁵M)–induced contractionswerereducedsigniﬁcantly.TheestimatedLD50was 1326mg/kgforFEO.Anydamageinthevitalorgansofthedead animalsdidnotreport.

TheteratogenicityofFEOwasinvestigatedontheratembryo limbbuds[41].TheresultsshowedthatFEOatalowconcentra- tion(0.93mg/ml)causedasignificantreductioninthenumberof staineddifferentiated foci.On theotherhand,FEO significantly diminisheddifferentiationathigherdoses,howeverparadoxically highdoseof3.72mg/mlcouldnotcauseasignificanteffect.They didnotobservestatisticaldifferenceinthenumberoffocibetween thecontrolgroupandtheexposedgrouptothe50␮lofethanol (asthehighestconcentrationofvehicle)in1mlofculturemedium.

TheysuggestthattheFEOattheappliedconcentrationsmayhave atoxiceffectonfetalcells,buttheydidnotreportanyevidenceof teratogenicity.

Inacohortstudyinvolving630pregnantwomen,collecteddata frommothersrevealedthatregularconsumptionoffennelduring pregnancycanleadtoshortergestationalageinwomencompared tonon-users[42].

4.3. Ginger(Zingiberofﬁcinale)

Gingerhasbeenusedworld-widelyagainstpregnancy-induced nauseaandvomitingduringthecenturies.However,itssafetyin pregnancyisstilldoubtfulandthereisacontinuousdebateonits application,especiallyintheﬁrsttrimester.

Theeffectofginger,acommonmorningsicknessremedy,on fetaldevelopmentinratwasinvestigated.Gingerproduces6-gin- gerol,whichgivesthespicytastetoginger.6-gingerolisthoughtto beapotentialteratogenicduetoitseffectonsomeessentialembry- onicdevelopmentalprocesses(i.e.disruptionofangiogenesis).Itis conﬁrmedbyitscapacitytoinhibittheproliferationandtubefor- mationofprimaryculturedhumanendothelialcellsthroughdown regulationofcyclidinDandalsoinhibitionoftumorgrowthinmice byitsanti-angiogenicactivity[43].Moreover,itcaninduceapopto- sis,DNAmutation,decreasecellmigrationandmotilityinadose dependentmanner,arrestingthecellcycleandstopcancercells proliferation.Therefore,itcanbeembryotoxicintheﬁrsttrimester whengingermightbetakentorelievemorningsickness.

Ina preclinicalstudy,20 or50g/Lginger teawereadminis- tered torats frompregnancy day6–15, throughtheir drinking water.Afterthesacriﬁceonday20,notoxicsignswereobserved inthemothers.However,theembryoniclossinthetreatedgroups wasdoublecomparedtocontrols.Thefetusesthatwereexposed togingerteaweresigniﬁcantlyheavierthancontrols;thiseffect wasmoreexpressedin femalefetusesand wasnot linkedwith increasedplacental size. Treatedfetuses alsoshowed advanced skeletaldevelopment[44].Theresultssuggestthatinuteroexpo- sure toginger tea resultsin increased earlyembryo loss with increasedgrowthinsurvivingfetuses.630pregnantwomenwith gingerintakewereparticipatedinastudyfor4yearsinanItalian publichospital.Shortergestationalageandsmallercircumference ofthenewborn’sskullwereobserved[42].

Althoughaccordingtodatafrom1966untilSeptember2004, gingerhasbeenproposedasasafeandefﬁcaciousalternativeto conventional antiemeticdrugs[45],someopinionssuggestthat itwouldbeprudenttoavoidusingeithergingeroritsextracted compounds[46].Ontheotherhand,thegreatestreviewaboutthe applicationofgingerin pregnancyclaimsthatgingerissafefor nauseaandvomitingintheﬁrsttrimester.EventheAmericanCol- legeofObstetricianandGynecologistsandtheU.K.NationalHealth Servicehaveacceptedgingerasanapplicableantiemeticinearly pregnancy[47].

Table1

Classiﬁcationofherballaxativeandantiemeticaccordingtotheirsafety.

Safety

Therapeuticuse Safetouse Usewithprecaution Moreevidenceis required,not recommended

Forbidden Nohumandataare

available

Laxative -Senna Flaxseed(2ndand

3rdtrimester)

Fenugreek – -Rhubarb

-Flaxseed(1st trimester)

Antiemetic Ginger(1st

trimester)

Fennel,Ginger(2nd and3rdtrimester)

– -Cannabis –

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5. Conclusion

Fromancient timesuntiltoday herbalmedicines hada long journey from being a medicine at that time to becoming a healthyremedysourceinthe21stcentury.Regardingallthemen- tionedstudiesandinvestigations,contrarytopopularbelief,herbal medicinescannotbesafeallthetime,especiallyduringpregnancy.

A conclusion of gestational safety of herbal laxatives and antiemeticsis showninTable1.During pregnancythemajority oftheherbaldrugsforconstipationcanbeharmful,especiallyif theyhavebeentakenintheﬁrsttrimester.Availableclinicalevi- denceprovesthattheonlyharmlessgestationalherballaxativeis sennausingeventhroughthewholegestationalperiod.Themost harmfulherbaldrugwhichiscommonlyusedbypregnantwomen (cannabis)canbeteratogenicandembryotoxicevenatlowdoses andthereforeitsuseasanantiemeticisnotrecommended.How- ever,gingerseemstobesafeasagestationalantiemetic,butonly inearlypregnancy.

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