special populations: pregnancy and breastfeeding · objectives describe the maternal changes that...

Special Populations:Special Populations:Pregnancy and Pregnancy and BreastfeedingBreastfeeding

Joanne C. Witsil, RN, PharmD, BCPSJoanne C. Witsil, RN, PharmD, BCPS

Clinical Pharmacist, General Medicine/Surgery and Family MedicinClinical Pharmacist, General Medicine/Surgery and Family MedicineeJohn H. Stroger Jr. Hospital of Cook CountyJohn H. Stroger Jr. Hospital of Cook County

Adjunct Clinical Assistant ProfessorAdjunct Clinical Assistant ProfessorUniversity of Illinois at Chicago, College of Pharmacy University of Illinois at Chicago, College of Pharmacy

Scenario 1Scenario 1

A 28 year old female walks into your A 28 year old female walks into your practice setting with a prescription that she practice setting with a prescription that she received 4 days ago from another received 4 days ago from another Practitioner for complaints of a urinary Practitioner for complaints of a urinary tract infection (UTI)tract infection (UTI)

RX written as Ciprofloxacin 500 mg po every RX written as Ciprofloxacin 500 mg po every 12 hours for 7 days12 hours for 7 days

ObjectivesObjectivesDescribe the maternal changes that occur during Describe the maternal changes that occur during pregnancy and how they affect drug absorption, pregnancy and how they affect drug absorption, distribution, metabolism and clearance distribution, metabolism and clearance Explain the characteristics of the placenta and Explain the characteristics of the placenta and lactation that impact drug distribution lactation that impact drug distribution State the 5 pregnancy categoriesState the 5 pregnancy categoriesDiscuss the current treatment regimens for Discuss the current treatment regimens for pregnant patients exposed to a biological, pregnant patients exposed to a biological, chemical or nuclear event chemical or nuclear event

Stages of PregnancyStages of Pregnancy

First trimester (weeks 1First trimester (weeks 1--12)12)Organogenesis occurs especially 5Organogenesis occurs especially 5--1010thth week week

AKA: embryonic period (first 8 weeks)AKA: embryonic period (first 8 weeks)

Second trimester (weeks 13Second trimester (weeks 13--26)26)Organs become functional Organs become functional

AKA: fetal period (actually starts week 9)AKA: fetal period (actually starts week 9)

Third trimester (weeks 27Third trimester (weeks 27--40)40)AKA: fetal/perinatal periodAKA: fetal/perinatal period

Dipiro JT, et al. Pharmacotherapy, A pathophysiologic approach. 5th ed. Chapter 78.

Katzung BG, et al. Basic & Clinical Pharmacology. 7th ed. Chapter 60.

Pregnancy Physiological Pregnancy Physiological changes changes

General ChangesGeneral ChangesSusceptibility to infections are altered Susceptibility to infections are altered

Overall, diminished cellOverall, diminished cell--mediated immunitymediated immunitySpecifically, neutrophil chemotaxis, adherence and Specifically, neutrophil chemotaxis, adherence and natural killer cell activity are decreasednatural killer cell activity are decreased

Mother and fetus are at greater risk for Mother and fetus are at greater risk for infectionsinfections

White SR, et al. Emerg Med Clin N Am 2002:20;365-92.

Maternal Pharmacokinetic Maternal Pharmacokinetic ChangesChanges

AbsorptionAbsorptionGastrointestinal tract (GIT) motility reducedGastrointestinal tract (GIT) motility reducedIncreased gastric pHIncreased gastric pHIncreased pulmonary alveolar drug uptakeIncreased pulmonary alveolar drug uptake

Key point: May lead to increased drug Key point: May lead to increased drug absorptionabsorption


DistributionDistributionPlasma volume increases by 50%Plasma volume increases by 50%

40% distributed to maternal compartments40% distributed to maternal compartments60% distributed to amniotic fluid, placenta, fetus60% distributed to amniotic fluid, placenta, fetus

Serum albumin levelSerum albumin levelDecreases as weeks of gestation increaseDecreases as weeks of gestation increase

Key point: more unbound or free drug in Key point: more unbound or free drug in circulation circulation

Especially drugs bound to serum albumin Especially drugs bound to serum albumin


MetabolismMetabolismIncreased progesterone and estradiol concentrations Increased progesterone and estradiol concentrations affect hepatic drug metabolismaffect hepatic drug metabolism

Either increased or decreasedEither increased or decreased

ClearanceClearanceRenal blood flow and glomerular filtration rate is Renal blood flow and glomerular filtration rate is increased by 25increased by 25--50%50%

Key point: appears these changes do not have Key point: appears these changes do not have clinical significance therefore no dose clinical significance therefore no dose adjustment! adjustment!


Placental Characteristics Placental Characteristics

Historically Historically Placenta was once thought of as a barrierPlacenta was once thought of as a barrier

FundamentallyFundamentallyBy 5By 5thth week of gestation it fully functions as a week of gestation it fully functions as a transporter between mother and fetus transporter between mother and fetus Most drugs move across membranes by Most drugs move across membranes by passive diffusionpassive diffusion

Mother to fetus and then once maternal serum Mother to fetus and then once maternal serum levels decline back to mother from fetuslevels decline back to mother from fetus


Specifically Specifically Maternal transplacental considerationsMaternal transplacental considerations

Maternal doseMaternal doseRoute of administrationRoute of administrationMaternal pharmacokineticsMaternal pharmacokinetics

Drug transplacental considerationsDrug transplacental considerationsHigh lipophilicityHigh lipophilicityLow ionizationLow ionizationLow molecular weightLow molecular weightLow protein bindingLow protein binding


Timing of exposureTiming of exposureTeratogenicity definitionTeratogenicity definition

It is the abnormal development of the fetus or fetal It is the abnormal development of the fetus or fetal organs either structurally or functionally. Abnormalities organs either structurally or functionally. Abnormalities can include the loss of pregnancy, structural or functional can include the loss of pregnancy, structural or functional abnormalities and uterine growth impairment abnormalities and uterine growth impairment

Embryonic period (2Embryonic period (2--88thth week of gestation)week of gestation)Greatest potential to cause organ structural damageGreatest potential to cause organ structural damage

Fetal period (9Fetal period (9thth weekweek--full term)full term)More subtle changes in function or behavior More subtle changes in function or behavior

Dipiro JT, et al. Pharmacotherapy, A pathophysiologic approach. 5th ed. Chapter 78. Katzung BG, et al. Basic & Clinical Pharmacology. 7th ed. Chapter 60.

Lactation CharacteristicsLactation Characteristics

Entrance into breast milkEntrance into breast milkDrugs enter via passive diffusion (most common) or Drugs enter via passive diffusion (most common) or active transportactive transport

Amount of drug passing via passive diffusion in most cases is Amount of drug passing via passive diffusion in most cases is directly proportional to maternal serum concentration directly proportional to maternal serum concentration In literature may be expressed as milk: plasma ratio (ratio of In literature may be expressed as milk: plasma ratio (ratio of 1 means equal amount)1 means equal amount)

pH of breast milk is more acidic than plasmapH of breast milk is more acidic than plasmaWeak basic drugs enter more freelyWeak basic drugs enter more freely

Dipiro JT, et al.. Pharmacotherapy, A pathophysiologic approach. 5th ed. Chapter 78.Briggs GG, et al. Drugs in pregnancy and lactation. 5th ed. Pages xiii-xviiii.

Lipophilic drugs enter more freelyLipophilic drugs enter more freelyConcentrate more in hindConcentrate more in hind--milk versus foremilk versus fore--milkmilk

Drugs that bind either to the proteins or onto the milk Drugs that bind either to the proteins or onto the milk fat globule enter more freely fat globule enter more freely

Timing and frequency of NursingTiming and frequency of NursingFirst few minutes of feed vs lastFirst few minutes of feed vs lastTiming of drug ingestion vs onset of feedTiming of drug ingestion vs onset of feed

It is still questionable how much the infant actually It is still questionable how much the infant actually ingests!ingests!

Dipiro JT, et al.. Pharmacotherapy, A pathophysiologic approach. 5th ed. Chapter 78.Briggs GG, et al. Drugs in pregnancy and lactation. 5th ed. Pages xiii-xviiii.

FDA Pregnancy CategoriesFDA Pregnancy Categories

Nahum GG, et al. Obstet Gynecol 2006;107:1120-38.

Treatment for BioterrorismTreatment for Bioterrorism

No treatment Treatment

Outcomes?

Quarantine?

Outcomes?

Adverse drug effects?

No TreatmentNo TreatmentClass A AgentClass A Agent Fatality Rates in the Fatality Rates in the

General Population General Population Fatality Case Reports Fatality Case Reports

in Pregnancyin Pregnancy

AnthraxAnthrax Cutaneous & GI Cutaneous & GI --2020--60%60%Inhalation Inhalation -- >80%>80%

3 cases 3 cases –– all diedall died

PlaguePlague Bubonic Bubonic -- 6060--90%90% 13/14 13/14 –– fetal lossfetal loss1 report in 1903 1 report in 1903 ––universal fetal loss universal fetal loss

SmallpoxSmallpox MajorMajor-- 2727--30%30%MinorMinor-- ~1%~1%

MajorMajor-- 63%63%Prior to 25Prior to 25thth weekweek-- 75% 75% stillbirthsstillbirths>25>25thth weekweek-- 60% lost60% lostBirthBirth-- 50% died within 2 50% died within 2 weeksweeks

Viral hemorrhagic FeverViral hemorrhagic Fever EbolaEbola-- 77%77%LassaLassa-- 11--36%36%

EbolaEbola-- 95.5%95.5%LassaLassa-- 3030--75%75%Both had fetal loss Both had fetal loss reported as 23reported as 23--66%66%

Hassett DE. J. Reprod. Immunol. 2003;60:13.24.Adapted from www.idph.state.il.us/Bioterrorism/otherlinks.htm

White SR, et al. Emerg Med Clin N Am 2002;20:365-92.

Kadanalo A, et al. CID 2003;36:1343-6.

http://www.idph.state.il.us/Bioterrorism/otherlinks.htm

No TreatmentNo TreatmentClass B AgentClass B Agent Fatality Rates in Fatality Rates in

General Population General Population Fatality Case Reports Fatality Case Reports

in Pregnancyin Pregnancy

BrucellosisBrucellosis 5%5% 11stst & 2& 2ndnd trimestertrimester-- 43% 43% fetal lossfetal loss3th trimester3th trimester-- 2% fetal 2% fetal lossloss

Q FeverQ Fever LowLow Spontaneous Abortion Spontaneous Abortion --22%22%Premature birthPremature birth-- 30%30%Growth restrictionGrowth restriction-- 69%69%Utero fetal deathUtero fetal death-- 7%7%

RicinRicin HighHigh 1 case report1 case report-- Infant Infant born with moderate born with moderate growth retardation & growth retardation & craoniocraonio--facial facial dysmorphia dysmorphia

www.idph.state.il.us/Bioterrorism/otherlinks.htmAdapted from . Hellmeyer L, et al. Z Geburtshilfe Neonatol. 2002 Sept-Oct;206:193-198. EL Mauhoub M, et al. Ann Trop Paediat. 1983 Jun;3:57-61. Khan MY, et al. Clin Infect Dis. 2001 Apr 15;32:1172-7.


Treatment of Class A and B Treatment of Class A and B Bacterial AgentsBacterial Agents

BacteriaBacteria Primary ChoicePrimary Choice AlternativeAlternativeAnthraxAnthrax Ciprofloxacin or doxycycline Ciprofloxacin or doxycycline

and 1 or 2 alternativesand 1 or 2 alternativesrifampin, vancomycin , rifampin, vancomycin , chloramphenicol, imipenem, chloramphenicol, imipenem, clindamycin, clarithromycin, clindamycin, clarithromycin, (PCN & ampicillin only once (PCN & ampicillin only once sensitivities confirmed) sensitivities confirmed)

PlaguePlague GentamicinGentamicin Ciprofloxacin or doxycycline Ciprofloxacin or doxycycline

TularemiaTularemia Gentamicin or streptomycinGentamicin or streptomycin Ciprofloxacin or doxycyclineCiprofloxacin or doxycycline

BrucellosisBrucellosis TMP/SMX and streptomycin TMP/SMX and streptomycin or rifampinor rifampin

None givenNone given

GlandersGlanders TMP/SMX and ceftazidime TMP/SMX and ceftazidime if severe diseaseif severe disease

TMP/SMX or tetracycline orTMP/SMX or tetracycline oramoxicillin/clavulanate in amoxicillin/clavulanate in mild diseasemild disease

Q FeverQ Fever Doxycycline or tetracyclineDoxycycline or tetracycline Quinilones, TMP/SMX Quinilones, TMP/SMX chloramphenicol chloramphenicol

Inglesby, TV, et al. JAMA 2000;283:2281-2290.

Adapted from www.idph.state.il.us/Bioterrorism/otherlinks.htm

Inglesby TV, et al. JAMA 2002;287:2236-2252. www.cdc.gov

*Dosing regimens are the same as for adults. See treatment guidelines available at IDPH or CDC.


Most Common Antibiotics Most Common Antibiotics AntibioticAntibiotic FDA FDA

CategoryCategoryPlacentaPlacentacrossing crossing

Excreted in Excreted in Breast MilkBreast Milk

Adverse Adverse drug drug

reactionreaction**AmoxicillinAmoxicillin BB YesYes YesYes Reported Reported

association with association with necrotizing necrotizing enterocolitis in enterocolitis in newbornsnewborns

ChloramphenicolChloramphenicol CC YesYes YesYes BMS, Caution if BMS, Caution if used near birth, used near birth, GrayGray--baby baby syndromesyndrome

CiprofloxacinCiprofloxacin CC YesYes YesYes ArthropathyArthropathy

DoxycyclineDoxycycline DD YesYes YesYes Fetal dental Fetal dental enamel enamel hypoplasia and hypoplasia and retarded skeletal retarded skeletal growth. Maternal growth. Maternal hepatic necrosishepatic necrosis

*Related to maternal/ fetal effects in human data. Briggs GG, et al. Drugs in pregnancy and lactation. 5th ed. Nahum GG, et al. Obstet Gynecol 2006;107:1120-38.


AntibioticAntibiotic FDA FDA CategoryCategory

PlacentaPlacentacrossing crossing



reactionreaction**GentamicinGentamicin CC YesYes YesYes No ototoxicity or No ototoxicity or

nephrotoxicity nephrotoxicity reported in reported in human fetuses. human fetuses. 1 case of renal 1 case of renal cystic dysplasiacystic dysplasia

PenicillinPenicillin BB YesYes YesYes No No rate of rate of congenital congenital anomaliesanomalies

RifampinRifampin CC YesYes YesYes Some reports of Some reports of congenital congenital anomaliesanomalies

VancomycinVancomycin BB YesYes YesYes No reports of No reports of congenital congenital anomalies. 1 anomalies. 1 report of report of bradycardia with bradycardia with rapid infusion.rapid infusion.

*Related to maternal/ fetal effects in human data.Briggs GG, et al. Drugs in pregnancy and lactation. 5th ed. Nahum GG, et al. Obstet Gynecol 2006;107:1120-38.

AntibioticAntibiotic FDA FDA CategoryCategory

PlacentaPlacentacrossing crossing



reactionreaction**CeftazidimeCeftazidime BB YesYes YesYes No increased No increased

risk of risk of congenital congenital anomaliesanomalies

StreptomycinStreptomycin DD YesYes YesYes Rare reports of Rare reports of irreversible irreversible deafness with deafness with fetal exposurefetal exposure

TetracyclineTetracycline DD YesYes YesYes Fetal dental Fetal dental enamel enamel hypoplasia and hypoplasia and retarded skeletal retarded skeletal growth. Reports growth. Reports of liver toxicity in of liver toxicity in mother.mother.

TMP/SMXTMP/SMX(Bactrim)(Bactrim)

C/D at termC/D at term YesYes YesYes Reports of Reports of congenital congenital anomalies. anomalies. Kernicterus if Kernicterus if used at birthused at birth

*Related to maternal/ fetal effects in human data. Briggs GG, et al. Drugs in pregnancy and lactation. 5th ed.

PostPost--exposure Prophylaxisexposure ProphylaxisBacteriaBacteria Primary Choice Primary Choice AlternativesAlternatives

AnthraxAnthrax Ciprofloxacin or doxycyclineCiprofloxacin or doxycycline Amoxiciliin only after 10Amoxiciliin only after 10--14 14 days of primary agentsdays of primary agents

PlaguePlague Ciprofloxacin or doxycyclineCiprofloxacin or doxycycline Chloramphenicol or Chloramphenicol or tetracyclinetetracycline

TularemiaTularemia Ciprofloxacin or doxycyclineCiprofloxacin or doxycycline

Q FeverQ Fever Doxycycline or TetracyclineDoxycycline or Tetracycline CiprofloxacinCiprofloxacin

*Dosing regimens are the same as for adults. See treatment guidelines available at IDPH or CDC.No prophylaxis recommended for brucellosis or glanders.




Treatment of Class A Viral Treatment of Class A Viral AgentsAgents

VirusVirus Primary ChoicePrimary Choice AlternativeAlternative

BotulismBotulism SupportiveSupportive Antitoxin trivalent (A,B,E) Antitoxin trivalent (A,B,E) from CDCfrom CDC

SmallpoxSmallpox SupportiveSupportive A few reports show in vitro A few reports show in vitro activity against smallpox by activity against smallpox by Cidofovir. May consider in Cidofovir. May consider in

severe cases severe cases Antibiotics only if secondary Antibiotics only if secondary

bacterial infections bacterial infections

Viral Hemorrhagic FeversViral Hemorrhagic Fevers SupportiveSupportive Ribavirin, not FDA approved Ribavirin, not FDA approved but could consider in severe but could consider in severe

casescases

*Dosing regimens are the same as for adults. See treatment guidelines available at IDPH or CDC.


Bronze MS, et al. Curr Opin Investig Drugs. 2003 Feb;4:172-8.


Most Common AntiviralsMost Common AntiviralsAntiviralAntiviral FDA FDA




reactionreaction**AntitoxinAntitoxin C for A & BC for A & B ?? UnknownUnknown Fetal Fetal

malformations malformations noted in animal noted in animal studies. studies. Hypersensitivity Hypersensitivity reactions. reactions.

CidofovirCidofovir CC Presumed YesPresumed Yes Presumed YesPresumed Yes Skeletal Skeletal malformations malformations noted in animal noted in animal

studies. No studies. No reports in reports in humanshumans

RibavirinRibavirin XX Presumed YesPresumed Yes No data No data availableavailable

Teratogenic Teratogenic effects in nearly effects in nearly

all animal all animal studiesstudies

*Related to maternal/ fetal effects in human data.

Briggs GG, et al. Drugs in pregnancy and lactation. 5th ed. Adapted from www.cdc.gov



PostPost--exposure Prophylaxisexposure Prophylaxis

VirusVirus Primary ChoicePrimary Choice AlternativeAlternative

BotulismBotulism No prophylaxisNo prophylaxis

SmallpoxSmallpox Smallpox vaccine Smallpox vaccine

Viral Hemorrhagic FeversViral Hemorrhagic FeversNo prophylaxisNo prophylaxis



Smallpox VaccineSmallpox Vaccine

Currently, under “peaceful” timesCurrently, under “peaceful” timesCDC does NOT recommend smallpox vaccine CDC does NOT recommend smallpox vaccine to the following:to the following:

Pregnant womenPregnant womenWomen who plan on becoming pregnant in 4 Women who plan on becoming pregnant in 4 weeks after vaccinationweeks after vaccinationWomen who are actively breastfeeding, excretion Women who are actively breastfeeding, excretion into breast milk unknowninto breast milk unknown

FDA pregnancy category CFDA pregnancy category C


www.cdc.gov/smallpox

Maternal adverse vaccine reactionsMaternal adverse vaccine reactionsPrimary vacciniaPrimary vaccinia-- vesicle at site of inoculationvesicle at site of inoculationEncephalitisEncephalitis-- a few reportsa few reportsVaccinia necrosumVaccinia necrosum

Fetal complicationsFetal complicationsCongenital defectsCongenital defectsViremiaViremiaFetal vacciniaFetal vaccinia

Rare but serious complication Rare but serious complication →→ fetal lossfetal loss

White SR, et al. Emerg Med Clin N Am 2002;20:365-92.www.cdc.gov/smallpox

Chemical TerrorismChemical TerrorismTypes of Nerve AgentsTypes of Nerve Agents

Tabun (GA)Tabun (GA)Sarin (GB)Sarin (GB)Soman (GD)Soman (GD)VXVX

SymptomsSymptomsMild/ModerateMild/Moderate

Include localized sweating, muscle fasciculations, nausea, Include localized sweating, muscle fasciculations, nausea, vomiting, weakness, dyspnea vomiting, weakness, dyspnea

Severe Severe Include unconsciousness, convulsions, apnea, flaccid Include unconsciousness, convulsions, apnea, flaccid paralysis paralysis

www.atsdr.cdc.gov/MHMI/mmg166.html

Chemical TreatmentChemical Treatment

Protect yourselfProtect yourselfPersonal Protective Equipment (PPE)Personal Protective Equipment (PPE)

If possibleIf possibleGet patient to remove contaminated clothing Get patient to remove contaminated clothing Place in a plastic bagPlace in a plastic bag

www.atsdr.cdc.gov/MHMI/mmg166.html

Agents UsedAgents UsedAntibioticAntibiotic FDA FDA




reactionreaction**

AtropineAtropine CC YesYes ControversialControversial Some reports of Some reports of congenital congenital

malformations malformations

22--PAMPAM CC UnknownUnknown UnknownUnknown Unknown if Unknown if causes fetal causes fetal harmharm

BenzodiazepinesBenzodiazepines

Diazepam is Diazepam is most commonmost common

DD YesYes YesYes Congenital Congenital malformations malformations noted, growth noted, growth retardation, retardation,

central nervous central nervous defectsdefects

*Related to maternal/ fetal effects in human data.

Briggs GG, et al. Drugs in pregnancy and lactation. 5th ed. Protopam Chloride (pralidoxime chloride) package insert.

Nuclear TerrorismNuclear TerrorismRadioactive iodine if released into airRadioactive iodine if released into air

It enters the body and is quickly taken up by thyroid It enters the body and is quickly taken up by thyroid gland gland

MaternalMaternal--fetal exposurefetal exposureEnters expecting mother passes through the placenta Enters expecting mother passes through the placenta →→ fetusfetusCan be passed through breastfeedingCan be passed through breastfeedingLower radiation doses are seen in fetusLower radiation doses are seen in fetusFetus thyroid glands are at more risk for injury Fetus thyroid glands are at more risk for injury

Severe consequences to fetusSevere consequences to fetusGrowth retardation, malformations, impaired brain function, Growth retardation, malformations, impaired brain function, cancer cancer

www.bt.cdc.gov/radiation

TreatmentTreatment

Potassium Iodide (KI)Potassium Iodide (KI)Everyone should take itEveryone should take it

Pregnant womenPregnant womenLactating womenLactating women

How does it work?How does it work?Blocks radioactive iodine from entering the thyroidBlocks radioactive iodine from entering the thyroidDoes not protect other parts of the body, ONLY Does not protect other parts of the body, ONLY thyroidthyroid


Dose KI (Pregnant and breastfeeding women)Dose KI (Pregnant and breastfeeding women)130mg orally with tablets or Two ml of solution130mg orally with tablets or Two ml of solutionTablets are 65mg or 130mgTablets are 65mg or 130mgSolutionSolution-- each 1 ml contains 65mg each 1 ml contains 65mg Protects thyroid gland for 24 hours Protects thyroid gland for 24 hours

Adverse drug effectsAdverse drug effectsAllergic reactions (check if allergic to iodine)Allergic reactions (check if allergic to iodine)GI upsetGI upsetRashesRashesInflammation of the salivary glandsInflammation of the salivary glands


Scenario 2Scenario 2

A 28 year old female walks into your A 28 year old female walks into your practice setting with a prescription that she practice setting with a prescription that she received 4 days ago from another received 4 days ago from another Practitioner for complaints of a cutaneous Practitioner for complaints of a cutaneous Anthrax exposure that is confirmed in your Anthrax exposure that is confirmed in your areaarea

RX written as Ciprofloxacin 500mg po every RX written as Ciprofloxacin 500mg po every 12 hours for 60 days12 hours for 60 days

Questions?

Additional ReferencesAdditional ReferencesKadanali A, et al. CID 2003;36:1343-6.Hellmeyer L, et al. Z Geburtshilfe Neonatol. 2002 Sep-Oct;206:193-8. Article in German.Wong TW. Trop Doc. 1986;16:187-89.Welty TK, et al. West J Med 1985;142:641-46.Ozbay K, et al. Clin Exp Obstet Gynecol. 2006;33:61-62.Giannacopoulos I, et al. Doi:10.1053/jinf.2002.1033,available online at www.idealibrary.comBerkovitch et al. Obstet Gynecol 1994;84:535-38.Moskovitz et al. Am J Gastroenterology 2004 Apr;99:656-61.Czeizel et al. Obstet Gynecol 1997;89:524-28.

http://www.idealibrary.com/

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