DRUG THERAPY DRUG THERAPY DURING PREGNANCYDURING PREGNANCY

Drugs that a pregnant woman takes can Drugs that a pregnant woman takes can affect theaffect the fetus in several ways: fetus in several ways:

1- They can act directly on the fetus causing damage 1- They can act directly on the fetus causing damage or abnormal development leading to birth defects or or abnormal development leading to birth defects or death. death.

Drugs can also alter the function of the placenta Drugs can also alter the function of the placenta usually by constricting blood vessels and reducing the usually by constricting blood vessels and reducing the blood supply of oxygen and nutrients to the fetus from blood supply of oxygen and nutrients to the fetus from mother and thus resulting in a baby that is underweight mother and thus resulting in a baby that is underweight and underdevelopedand underdeveloped..

Moreover they can cause the muscles of the uterus to Moreover they can cause the muscles of the uterus to contract forcefully; indirectly injuring the fetus by contract forcefully; indirectly injuring the fetus by reducing the blood supply or triggering pre-term labor reducing the blood supply or triggering pre-term labor and delivery. and delivery.

PHARMACOKENETICS OF PHARMACOKENETICS OF DRUGS DURING DRUGS DURING PREGNANCYPREGNANCY ABSORPTION- DECREASED GI ABSORPTION- DECREASED GI

MOTILITY CAUSES INCREASED DRUG MOTILITY CAUSES INCREASED DRUG ABSORPTION.ABSORPTION.

DISTURBUTION- PROTIEN BINDING IS DISTURBUTION- PROTIEN BINDING IS DECREASED CAUSES INCREASED DECREASED CAUSES INCREASED FREE DRUG TO BE AVAILABLE.FREE DRUG TO BE AVAILABLE.

METABOLISM-INCREASED HEPATIC METABOLISM-INCREASED HEPATIC METABOLISM OCCURS FOR SOME METABOLISM OCCURS FOR SOME DRUGSDRUGS

PHARMACOKENETICSPHARMACOKENETICS

EXCRETION- IN THE 3RD TRIMESTER EXCRETION- IN THE 3RD TRIMESTER INCREASED RENAL BLOOD FLOW & INCREASED RENAL BLOOD FLOW & GFR CAUSES SOME DRUGS TO GFR CAUSES SOME DRUGS TO CLEAR THE BODY FASTER.CLEAR THE BODY FASTER.

DRUG THERAPY IN THE DRUG THERAPY IN THE CHILDBEARING CLIENTCHILDBEARING CLIENT

REQUIRES SPECIAL REQUIRES SPECIAL CONSIDERATIONSCONSIDERATIONS

IS CHALLENGING TO IS CHALLENGING TO PROVIDE PROVIDE EFFECTIVE EFFECTIVE Treatment WHILE Treatment WHILE AVOIDING HARM TO AVOIDING HARM TO EMBRYO, FETUS OR EMBRYO, FETUS OR NEONATENEONATE

CENTERED ON CENTERED ON RISK/BENEFIT RISK/BENEFIT RATIORATIO

EFFECTS OF EFFECTS OF DRUGS NOT DRUGS NOT ALWAYS KNOWNALWAYS KNOWN

ANY DRUG TAKEN BY ANY DRUG TAKEN BY THE PREGNANT OR THE PREGNANT OR BREAST FEEDING BREAST FEEDING CLIENT HAS THE CLIENT HAS THE POTENTIAL TO POTENTIAL TO REACH THE FETUS REACH THE FETUS BY WAY OF BY WAY OF MATERNAL MATERNAL CIRCULATION OR CIRCULATION OR NEONATE BY WAY OF NEONATE BY WAY OF BREASTMILKBREASTMILK

EFFECTS OF DRUGS EFFECTS OF DRUGS ON THE EMBRYO, ON THE EMBRYO, FETUS, OR NEONATEFETUS, OR NEONATE

MAY VARY---MAY VARY--- NO EFFECT.NO EFFECT. LITTLELITTLE SERIOUS- FETAL TOXICITYSERIOUS- FETAL TOXICITY SPONTANEOUS ABORTIONSPONTANEOUS ABORTION DEATHDEATH FETAL MALFUNCTIONFETAL MALFUNCTION FETAL MALFORMATIONS.FETAL MALFORMATIONS.

RECENT STUDIESRECENT STUDIES

75% OF PREGNANT CLIENTS USE 75% OF PREGNANT CLIENTS USE 3-10 DIFFERENT DRUGS 3-10 DIFFERENT DRUGS (PRESCRIPTION OR OTC’S) OTHER (PRESCRIPTION OR OTC’S) OTHER THAN VITAMINS/MINERAL THAN VITAMINS/MINERAL SUPPLEMENTS DURING THEIR SUPPLEMENTS DURING THEIR PREGNANCY.PREGNANCY.

OTC’S WERE USED 4 TIMES THAT OTC’S WERE USED 4 TIMES THAT OF PRESCRIPTION DRUGS.OF PRESCRIPTION DRUGS.

DRUG LEVELS IN THE DRUG LEVELS IN THE FETUS REACHED 50-FETUS REACHED 50-100% OF THE 100% OF THE MATERNAL BLOOD MATERNAL BLOOD LEVELSLEVELS

Inadvertent ExposureInadvertent Exposure 1/2 of pregnancies unplanned1/2 of pregnancies unplanned Teratogenic potential should be Teratogenic potential should be

considered and explained to women of considered and explained to women of childbearing age at time drug is childbearing age at time drug is prescribedprescribed– <50% of women know they are pregnant by <50% of women know they are pregnant by

44 thth week and ~20% still don’t know by 8 week and ~20% still don’t know by 8 thth week week

ComplianceCompliance Pregnant women tend to comply Pregnant women tend to comply

less than optimally with drug less than optimally with drug therapytherapy

39% of women reported 39% of women reported noncompliance predominantly noncompliance predominantly due to hesitation to use drugs due to hesitation to use drugs during pregnancyduring pregnancy

BIRTH DEFECTSBIRTH DEFECTS

INCIDENCE OF MAJOR STRUCTURAL INCIDENCE OF MAJOR STRUCTURAL DEFECTS (ABNORMALITIES) IS DEFECTS (ABNORMALITIES) IS ABOUT 6% OF ALL PREGNANCIES.ABOUT 6% OF ALL PREGNANCIES.

3% ARE CAUSED BY DRUGS OR 3% ARE CAUSED BY DRUGS OR ENVIRONMENTAL ENVIRONMENTAL fACTORS/EXPOSUREfACTORS/EXPOSURE

3% HAVE UNKNOWN CAUSES3% HAVE UNKNOWN CAUSES

BIRTH DEFECTSBIRTH DEFECTS 1/2 OF THE BIRTH DEFECTS ARE 1/2 OF THE BIRTH DEFECTS ARE

OBVIOUS AT BIRTH.OBVIOUS AT BIRTH. 1/2 OF THE BIRTH DEFECTS 1/2 OF THE BIRTH DEFECTS

AREN’T DISCOVERED UNTIL LATER AREN’T DISCOVERED UNTIL LATER IN LIFE OR DISCOVERED DURING IN LIFE OR DISCOVERED DURING AN AUTOPSYAN AUTOPSY

INCIDENCE OF MINOR INCIDENCE OF MINOR STRUCTURAL ABNORMALIES IS STRUCTURAL ABNORMALIES IS NOT KNOWN.NOT KNOWN.

TERATOGENICTERATOGENICTERATOGENESISTERATOGENESIS TERAS-”MONSTER”TERAS-”MONSTER” GENSIS-”PRODUCING”GENSIS-”PRODUCING” BIRTH DEFECTS/DISTORTION OF BIRTH DEFECTS/DISTORTION OF

GROSS ANATOMY.GROSS ANATOMY. EXAMPLES- CLEFT LIP/PALATE, EXAMPLES- CLEFT LIP/PALATE,

CLUBFOOT, NEURAL TUBAL CLUBFOOT, NEURAL TUBAL DEFECTS, MISSING OR DEFECTS, MISSING OR MALFORMED LIMBS/FINGERS.MALFORMED LIMBS/FINGERS.

TERATOGENICTERATOGENIC

ALSO-BEHAVORIAL AND/ OR ALSO-BEHAVORIAL AND/ OR BIOCHEMICAL ABNORMALITIES.BIOCHEMICAL ABNORMALITIES.

TERATOGENESIS MAYBE DIRECT TERATOGENESIS MAYBE DIRECT MALFORMATIONS OF MALFORMATIONS OF STRUCTURESSTRUCTURES

OR INDIRECT-SUCH AS OR INDIRECT-SUCH AS INTERFERING WITH OINTERFERING WITH O22 OR OR NUTRIENTS.NUTRIENTS.

FETAL EFFECTS FROM FETAL EFFECTS FROM DRUGS DEPEND ON DRUGS DEPEND ON SEVERAL FACTORSSEVERAL FACTORS

TIME- WHEN DRUG IS TAKEN IN TIME- WHEN DRUG IS TAKEN IN PREGNANCY.PREGNANCY.

1.1. PREIMPLANTATIONPREIMPLANTATION PERIOD; from PERIOD; from CONCEPTION TO 2 WEEKCONCEPTION TO 2 WEEK

HIGH DOSE- MAYBE HIGH DOSE- MAYBE LETHAL/DEATH/ABORTIONS.LETHAL/DEATH/ABORTIONS.

LOW DOSE-MAYBE NOTHING.LOW DOSE-MAYBE NOTHING.

2. 2. EMBRYONIC PERIOD-3-8 EMBRYONIC PERIOD-3-8 WEEKS WEEKS *FIRST TRIMESTER* 2-9 weeks *FIRST TRIMESTER* 2-9 weeksGROSS MALFORMATIONSGROSS MALFORMATIONS3. 3. FETAL PERIOD FETAL PERIOD 9-40 WEEKS (TERM)9-40 WEEKS (TERM)FUNCTION PROBLEMS RATHER FUNCTION PROBLEMS RATHER THAN GROSS ANATOMYTHAN GROSS ANATOMY LEARNING DEFICITS and OR LEARNING DEFICITS and OR BEHAVORIAL ABNORMALIESBEHAVORIAL ABNORMALIES

Known TeratogensKnown Teratogens Alcohol (Ethanol)Alcohol (Ethanol) CarbamazepineCarbamazepine Cytotoxic Cytotoxic

chemotherapychemotherapy DESDES Isotretinoin and Isotretinoin and

EtretinateEtretinate LithiumLithium

MethimazoleMethimazole MisoprostolMisoprostol PhenytoinPhenytoin ThalidomideThalidomide TrimethoprimTrimethoprim Valproic AcidValproic Acid WarfarinWarfarin

Drug pregnancy Drug pregnancy categoriescategories

Category ACategory A: Adequate and well-controlled : Adequate and well-controlled studies have failed to demonstrate a risk studies have failed to demonstrate a risk to the fetus in the first trimester of to the fetus in the first trimester of pregnancy (and there is no evidence of pregnancy (and there is no evidence of risk in later trimesters).risk in later trimesters).

Category BCategory B: Animal reproduction studies : Animal reproduction studies have failed to demonstrate a risk to the have failed to demonstrate a risk to the fetus and there are no adequate and well-fetus and there are no adequate and well-controlled studies in pregnant women.controlled studies in pregnant women.

Category CCategory C: Animal reproduction studies have : Animal reproduction studies have shown an adverse effect on the fetus and there shown an adverse effect on the fetus and there are no adequate and well-controlled studies in are no adequate and well-controlled studies in humans, but potential benefits may warrant use humans, but potential benefits may warrant use of the drug in pregnant women despite potential of the drug in pregnant women despite potential risks.risks.

Category DCategory D: There is positive evidence of : There is positive evidence of human fetal risk based on adverse reaction data human fetal risk based on adverse reaction data from investigational or marketing experience or from investigational or marketing experience or studies in humans, but potential benefits may studies in humans, but potential benefits may warrant use of the drug in pregnant women warrant use of the drug in pregnant women despite potential risks.despite potential risks.

Category X: Category X: Studies in animals or Studies in animals or humans have demonstrated fetal humans have demonstrated fetal abnormalities and/or there is positive abnormalities and/or there is positive evidence of human fetal risk based on evidence of human fetal risk based on adverse reaction data from adverse reaction data from investigational or marketing experience, investigational or marketing experience, and the risks involved in use of the drug and the risks involved in use of the drug in pregnant women clearly outweigh in pregnant women clearly outweigh potential benefits.potential benefits.

Category N: Category N: FDA has not classified the FDA has not classified the drug.drug.

Penici l l ins and Penici l l ins and CephalosporinsCephalosporins Amoxicillin and cephalosporins Amoxicillin and cephalosporins

(category B) are considered safe to use (category B) are considered safe to use during pregnancyduring pregnancy

No increased risk of malformations with No increased risk of malformations with amoxicillin/clavulanic acid (Augmentin) amoxicillin/clavulanic acid (Augmentin) in 2 studies. (category B) in 2 studies. (category B)

Erythromycin and azithromycin: Category Erythromycin and azithromycin: Category BB

Clarithromycin: Category CClarithromycin: Category C Clindamycin: category BClindamycin: category B Ciprofloxacin: category C: possibility of Ciprofloxacin: category C: possibility of

joint malformation (seen only in children) joint malformation (seen only in children) Tetracyclines: category D Tetracyclines: category D

MetronidazoleMetronidazole

Mutagenic in bacteria and Mutagenic in bacteria and carcinogenic in animalscarcinogenic in animals

Small number of reports raised Small number of reports raised suspicion of teratogenic effectsuspicion of teratogenic effect

Category BCategory B

Aminoglycosides: ototoxicity: can cause Aminoglycosides: ototoxicity: can cause deafnessdeafness

Sulfonamides: jaundice when given late in Sulfonamides: jaundice when given late in pregnancy and possible brain damage pregnancy and possible brain damage (kernictrus).(kernictrus).

Local Anesthetics - Local Anesthetics - LidocaineLidocaine Considered relatively safe for use Considered relatively safe for use

during pregnancy (category B)during pregnancy (category B) Mepivacane (category C)Mepivacane (category C)

EpinephrineEpinephrine Potential to compromise Potential to compromise

uterine blood flowuterine blood flow Studies have failed to Studies have failed to

demonstrate adverse fetal demonstrate adverse fetal effectseffects

Low doses used in dentistryLow doses used in dentistry Avoid inadvertent Avoid inadvertent

intravascular injectionintravascular injection Category CCategory C

AcetaminophenAcetaminophen ““Analgesic of choice” category B.Analgesic of choice” category B.

NSAIDS NSAIDS (including Aspirin and (including Aspirin and cox II- inhibitors)cox II- inhibitors)

Increased risk of miscarriage? Increased risk of miscarriage?

Avoid use during late pregnancy (3Avoid use during late pregnancy (3 rdrd trimester)trimester)� ↑↑ BleedingBleeding– Inhibition of prostaglandin synthesisInhibition of prostaglandin synthesis

Prolonged labourProlonged labour Constriction of ductus arteriosusConstriction of ductus arteriosus Category C but in last trimester category DCategory C but in last trimester category D

NarcoticsNarcotics(Codeine, Oxycodone, etc.)(Codeine, Oxycodone, etc.)

Don’t appear to Don’t appear to ↑↑ risk of birth risk of birth defectsdefects

Low dose short-term regimens Low dose short-term regimens acceptable. Category Cacceptable. Category C

If used for long period: category D If used for long period: category D Respiratory depressionRespiratory depression Neonatal withdrawalNeonatal withdrawal

Nitrous Oxide (NNitrous Oxide (N 22O) with O) with OO 22 Use during pregnancy somewhat Use during pregnancy somewhat

controversialcontroversial Inhibits methionine synthetase which can Inhibits methionine synthetase which can

affect DNA synthesisaffect DNA synthesis Teratogenic in animalsTeratogenic in animals Single brief maternal exposure during Single brief maternal exposure during

pregnancy unlikely to pose a substantial pregnancy unlikely to pose a substantial teratogenic riskteratogenic risk

Minimize prolonged use (< 30 minutes, at Minimize prolonged use (< 30 minutes, at least 50% Oleast 50% O22))

BenzodiazepinesBenzodiazepines

Category DCategory D Cause cleft palatCause cleft palat

RadiationRadiation In most cases of diagnostic x-In most cases of diagnostic x-

rays the fetal radiation exposure rays the fetal radiation exposure is much below the threshold dose is much below the threshold dose of 5 to 10 radof 5 to 10 rad

Average Fetal Exposure DoseAverage Fetal Exposure Dose (mrad)(mrad)

CXR <5

Abdomen 200-289

UGI 48-360

IVP 358-880

Dental 0.01

• Fetal exposure dose from a full mouth series Fetal exposure dose from a full mouth series (18 films) or panoramic radiograph is <1/1000 (18 films) or panoramic radiograph is <1/1000 value of concernvalue of concern• 40-fold < naturally occurring background 40-fold < naturally occurring background radiationradiation

American Dental American Dental AssociationAssociation Abdominal exposure during dental Abdominal exposure during dental

radiography is negligibleradiography is negligible Recommend that pregnant women Recommend that pregnant women

postpone elective dental x-rays until postpone elective dental x-rays until after delivery; however, there are times after delivery; however, there are times when an x-ray may be required during when an x-ray may be required during pregnancy to help diagnose and treat pregnancy to help diagnose and treat oral disease (thyroid collar and apron)oral disease (thyroid collar and apron)

Breast feeding drug Breast feeding drug administrationadministration

Most drugs that go into the body will also go into the Most drugs that go into the body will also go into the milk.milk.

so before any medication is taken, consideration of so before any medication is taken, consideration of its effect on baby and whether or not it has any its effect on baby and whether or not it has any effects on lactation needs to be done. effects on lactation needs to be done.

While most medications are safe to take while While most medications are safe to take while breastfeeding, it’s wise to talk to the doctor before breastfeeding, it’s wise to talk to the doctor before taking.taking.

Some drugs do not harm the baby, but may affect Some drugs do not harm the baby, but may affect the milk volume by suppressing the milk-making the milk volume by suppressing the milk-making hormones.hormones.

The effect of the drug wil l The effect of the drug wil l depend on:depend on:

••The route of administration: The route of administration: Topical medications (skin creams) and medications Topical medications (skin creams) and medications inhaled or applied to the eyes or nose reach the milk inhaled or applied to the eyes or nose reach the milk in lesser amounts and more slowly than other routes in lesser amounts and more slowly than other routes and are almost always safe for nursing mothers.and are almost always safe for nursing mothers. oral medications take longer to get into the milk than oral medications take longer to get into the milk than IV and IM routesIV and IM routes

••The amount The amount taken: The higher the dosage, the taken: The higher the dosage, the more the drug transfers into milk.more the drug transfers into milk.How often you take the drug: How often you take the drug: Medications taken 30 Medications taken 30 to 60 minutes before you feed are likely to be a to 60 minutes before you feed are likely to be a peak blood levels when your baby nurses.peak blood levels when your baby nurses.Your baby’s age and health: Your baby’s age and health: Premature infants Premature infants have immature kidney and liver functions and may have immature kidney and liver functions and may have trouble processing and eliminating even small have trouble processing and eliminating even small quantities of drugs that might not cause problems quantities of drugs that might not cause problems for larger, full-term infantsfor larger, full-term infantshowever, even full-term baby’s protective metabolic however, even full-term baby’s protective metabolic systems are not fully developed for the first week of systems are not fully developed for the first week of life. life.

Babies who are seriously ill, especially those with Babies who are seriously ill, especially those with immune system disorders, may have less ability to immune system disorders, may have less ability to metabolize the same amount of medication than a metabolize the same amount of medication than a healthy baby.healthy baby.••The frequency and volume of feedings: The frequency and volume of feedings: The baby who The baby who is nursing once or twice a day, and is supplemented the is nursing once or twice a day, and is supplemented the rest of the time, will receive less of a drug than the baby rest of the time, will receive less of a drug than the baby who is exclusively breastfed and may nurse 11 times a who is exclusively breastfed and may nurse 11 times a day.day.••Duration of drug therapy: Duration of drug therapy: A medication taken for weeks A medication taken for weeks or months may have a greater impact on nursing than or months may have a greater impact on nursing than one taken for just a few days.one taken for just a few days.

••The type of medication: The type of medication: Characteristics such as the Characteristics such as the molecular weight, how fat soluble the drug is, and molecular weight, how fat soluble the drug is, and how long it takes for it to be eliminated from your how long it takes for it to be eliminated from your system, or it’s half-life, all affect how much of the system, or it’s half-life, all affect how much of the drug is transferred into your milk.drug is transferred into your milk.

Aspirin in large doses – May cause bleeding or Aspirin in large doses – May cause bleeding or Reye’s syndrome in the Reye’s syndrome in the fetusfetus Chloramphenicol – Can cause diarrhea, bone Chloramphenicol – Can cause diarrhea, bone marrow suppression and gray baby syndromemarrow suppression and gray baby syndrome

Tetracyclines - the transfer of tetracyclines into breast milk is low but they are usually avoided due to the possible risks of inhibiting bone growth or causing dental staining.

Fluoroquinolones should also be avoided in breastfeeding as they have been reported to cause arthropathies in immature animals.

Sulphonamides such as sulphamethoxazole are unlikely to be problematical in high bilirubin and glucose -6-phosphate

MetronidazoleMetronidazole Use during lactation controversialUse during lactation controversial Excreted into breast milk in relatively large Excreted into breast milk in relatively large

amountsamounts Concern expressed with respect to possible Concern expressed with respect to possible

mutagenic effectsmutagenic effects No reports of adverse effects in nursing infantsNo reports of adverse effects in nursing infants In conventional doses compatible with In conventional doses compatible with

breastfeedingbreastfeeding If taken in single large dose breastfeeding may If taken in single large dose breastfeeding may

be temporarily withheld for 24 hoursbe temporarily withheld for 24 hours

CodeineCodeine Intermittent difficulty breastfeeding Intermittent difficulty breastfeeding

and lethargy and lethargy Blood morphine concentration very Blood morphine concentration very

highhigh

BenzodiazepinesBenzodiazepines Milk levels of benzodiazepines not Milk levels of benzodiazepines not

excessive but rarely sedation has been excessive but rarely sedation has been reported in breastfed infantsreported in breastfed infants

If sedative required, shorter half-life If sedative required, shorter half-life drugs such as lorazepam and drugs such as lorazepam and midazolam preferredmidazolam preferred

Long term exposure not recommendedLong term exposure not recommended

Drugs considered to be safeDrugs considered to be safe AcetaminophenAcetaminophen IbuprofenIbuprofen LidocaineLidocaine Penicillins and Cephalosporins, and macrolidesPenicillins and Cephalosporins, and macrolides