Belle-drugs in Pregnancy

8/17/2019 Belle-drugs in Pregnancy

1/17

DRUGS IN PREGNANCY

Epidemiology Maternal

Pharmacokinetics

etal pharmacokinetics Placental pharmacokinetics

In pregnancy, it is

estimated that eachwoman takes 1-3 drugs

beside vitamin

supplements or iron

About 1/3 of women in the

U take drugs at least once

during pregnancy!

"nly #$ take a drug during

the %rst trimester!

&here has been a

considerable reduction indrugs used in pregnancy

since the mid-1'#(s

))) *elf-administered drugs

from #+$ to '$

hanges in body

uid volume! hanges in .*

parameters!

hanges in

pulmonary

functions!

Alteration in gastric

activity!

hanges in serum

binding protein

concentrations! Alteration in kidney

function

lasma binding proteins

di0er from maternal sofree fractions of basic

drugs are elevated!

iver e2presses

metaboliing enymes,

but capacity less than the

mother!

4rugs transferred across

the placenta undergo 1st

pass hepatic e0ect

through the fetal liver! 5etal kidneys are still

immature!

5etal urine enters

amniotic uid which may

be swallowed by the fetus!

6lood ow through the placenta

7maternal side8 increasesduring gestation 79( ml/min at

1( weeks of pregnancy to #((

ml/min at 3: weeks8

ompounds that alter blood

ow alter maternal drug

disposition and placental

transfer!

lacental metabolism

7dealkylation, hydro2ylation,

demethylation8 a0ects drugstransfer across the placenta!

At term, the surface area of the

placenta is at its ma2imum and

nearly all substances can reach

the fetus!

Dr!g trans"er ;ost drugs have a molecular weight

below 1((( 4altons!

4rugs less than 1((o 4altons crossthe placenta7less than #(( 4altons

cross easily8

;ain determinant of the drug

concentration in the


2/17

the mother=s blood concentration!

"ther factors>

)ipid solubility and protein binding!

) 4egree of ioniation at physiologic

p?!

)placental blood ow and surface

area available for transfer!

&he processes that govern the passage

of a drug into milk are similar to

placental condition>

;aternal serum concentration is

the main determinant!

&he milk p? is slightly acidic

in comparison to serum p?@

so weak bases could become

trapped in milk 7 ion trapping 8!

&ype of e0ects on the fetus>

&eratogenecity- readily detected at,

or shortly after, birth 7thalidomide8!

ong term latency- 7 4

&he thri"ty phenotype hypothesis

says that reduced fetal growth is

strongly associated with a number of

chronic conditions later in life! &his

increased susceptibility results from

adaptations made by the fetus in an

environment limited in its supply of

nutrients! &hese chronic conditionsinclude coronary heart disease,

stroke, diabetes, and hypertension


3/17

76arker hypothesis> low birth weight

is associated with increased risk of

diabetes, hypertension and heart

disease in adulthood8!#eratogenesis Mal"ormations $rganogenesis

It is de%ned as structural orfunctional 7e!g! renal failure8

dysgenesis of the fetal organs!

&ypical manifestations include>

)congenital malformations with

varying severity!

)IUB!

)arcinogenesis!

)fetal demise!

In human, the critical time for drug-

induced congenital malformations is

in the %rst trimester!

4rug-induced to2icity can occur at

any time during gestation!

&he overall incidence of> ) ;aCor congenital malformations is

around 7D-38$

)minor malformations is '$

It has been estimated that>

)D9$ are due to genetic or

chromosomal abnormalities

)1($ due to environmental causes

including drugs!

)#9$ of unknown etiology!

&he part played by drugs is probably

small!

&he critical time for drug-inducedcongenital malformations is usually

the period of organogenesis

))about D( to 99 days after

conception!

))about 3+ to #' days 79-1( weeks8

after the %rst day of the last

menstrual period!

Interference in this process causes a

teratogenic e0ect!

If a drug is given after this time it will

not produce a maCor anatomical

defect, but more of a functional one!

Pregnancy Risk Categories &he drugs are classi%ed according to their risk factor category, and the de%nitions for each category are used by the 5ood

and 4rug Administration 754A8Category A Category % Category C Category D Category &

• ontrolled

studies in women

fail to demonstrate

a risk to the fetus in

• Animal reproduction

studies have failed

to demonstrate a

risk to the fetus and

• Animal

reproduction

studies have

shown an

• &here is positive

evidence of human

fetal risk based on

adverse reaction data

• *tudies in animals

or humans have

demonstrated fetal

abnormalities or


4/17

the %rst trimester,

there is no

evidence of a risk in

later trimesters,

and a remote

possibility of fetal

harm

• &he only few

medications

classi%ed as

category A are>

18


5/17


6/17

Diethylstil'esterol (DES) *itamin A analog!es• *ynthetic nonsteroidal estrogen that

was %rst synthesied in 1'3:, and

currently it is classi%ed as ategory F

drug

• It was prescribed during 1'+(-1'G(to prevent miscarriages in high risk

pregnancies by increasing the level of

estrogen and progesterone synthesis

by the placenta

• In 1'G1, it was discovered that

women between 1#-D( years old

developed vaginal adenocarcinoma,

that was linked to their intrauterine

fetal e2posure

• Appro2imately 1 in 1((( pregnancieswere e2posed, and G9$ of which

resulted in girls with vaginal and

cervical carcinomas as well as uterine

anomalies

• ;ale o0spring had abnormal genitalia

and sperm defects

• &he most common is isotretinoin,

used for the treatment of acne

• lassi%ed as category F

• &he teratogenic e0ects of retinoids on

animals were known for years beforetheir clinical use

• &he critical e2posure time is between

3-9 weeks of pregnancy

• Contracepti+e meas!res are o" at

least one month 'e"ore, d!ring

treatment, and no pregnancy "or

- years a"ter a co!rse o" the dr!g

• 5etal abnormalities have not been

associated with topical retinoids but it

is advised to avoid their use inpregnancy

• &eratogenic e0ects are seen in

up to D9$ of babies

• 9($ of a0ected children have

an IH below :9

• It was appro2imately recordedthat between 1':D and 1':G>

o ())*+,)) malformed children

o -))*+))) spontaneous

abortions

o .)))*-))) elective abortions

• &he embryopathy includes>

o #N" defects

o #raniofacial defects

o #ardiovascular defects

o Thymic defects

o 'iscellaneous defects

#halidomide• It is no longer used as an antiemetic

• It was used in the past by pregnant women in the 1st trimester when they start having nausea and vomiting

• &he mechanism of action is thought to be partly due to antiangiogenesis• 5etal e2posure caused high rates of abnormalities 7D(-3($8 that include>

o "evere limb shortening defects /phocomelia0

o 1oss of hearing2 facial paralysis2 anotia2 microtia

o enal malformations


7/17

o #ongenital heart disease

• It is now used for other diseases, such as drug-resistant multiple myeloma, cutaneous lupus erythematosis, erythema

nodosum leprosum, 6ehcet=s disease, and aposi sarcoma 7care must be needed if the patient is a woman in reproductive

age or likes to become pregnant8

Anti'iotics

Class o"Medication

Category % Category C Category D

Antibiotics AithromycinAtreonamCephalosporins

lavulanatelindamycin

"afe during the rst +4 weeks of

pregnancy

'inimal e5ect on bone but after 67

weeks of gestation2 discoloration of the

teeth and enamel hypoplasia occur

'aternal hepatotoxicity in the form of

acute fatty liver2 leading to death in

some cases where pregnant women

were treated with large doses

regnancy is not terminated if the

women was found to take them

.. Altho!gh in category C, gi+e concern "or /!oro0!inolone1

ind!ced "etal cartilage damage, as most o'stetricians a+oid

their !se in pregnancy


8/17

• &rimethoprim 7/48 is a theoretical teratogen as it is a

folic acid antagonist

• &he aminoglycosides748 can cause ototo2icity

•


9/17

Class o"Medication

Category % Category C

Anti"!ngals Amphotericin %Clotrima2ole

Caspo"!ngin

l!cona2oleGriseo"!l+in

3etocona2oleNystatin

#ercona2ole

&here is no obstacle in giving topical

antifungal agents, but systemic oral

medications are avoided

Antimalarial agents

• AtovaEuone/roguanil 78o Lo fetal harm in pregnant rats and rabbitso roguanil is considered to be the least to2ico Momen taking the drug either alone or in

combination should be supplemented with 5A

o *hould be used with caution in the %rst trimester

• hloroEuine 78o At high doses, it is embryo to2ic and teratogenic in

ratso hloroEuine should not be withheld during

pregnancy because the risk of comlications from

malarial infection in pregnancy is increasedo *afe to be breastfeed

• 78 ?ydro2ychloroEuine, ;eoEuine, rimaEuine,

yrimethamine, 4apsone, 4!?alofantrine

Anti+iral dr!gs


10/17

• Acyclovir 768o Lot fond to be teratogenic in pregnant mice, rats

and rabbitso robably safe in pregnancy and breastfeeding

• Amantidine 78

o 4ose-related teratogenicity in rats at doseseEuivalent to the human dose

o Lo fetal harm was observed in pregnant rabbitso 6irth defects have been observed in humans but the

data are very limitedo Avoid during lactation

• Anti-retroviral agentso Amprenavir 78, Indinavir 78, Lel%navir 76/8,

Bitonavir 76/8 and *aEuinavir 76/8 are protease

inhibitors used for the treatment of ?I. infectiono Lo evidence of teratogenicity has been observed

in animals 7e2ceptions of Indinavir8o 6ene%t outweigh risks

• Nidovudine 7for ?I. positive8 category , must be given

for the pregnant woman if she is ?I.Ove

Anticoag!lants4ar"arin (D)

• It is contraindicated in pregnancy, as it

crosses the placenta and may cause

bleeding in the fetus

• Its use in pregnancy is commonly

associated in with spontaneous

abortions, stillbirth, neonatal death,

and preterm birth

• oumarins 7such as warfarin8 are

also teratogens@ the incidence of birth

defects in infants e2posed to

warfarin in utero appears to be around

9$, although higher %gures 7up to

3($8 have been reported in some

studies

• Marfarin administration in the second

and third trimesters is much less

commonly associated with birth

defects, and when they do occur, are

etal 4ar"arin Syndrome (4S)

• Aka dysmorphism due to warfarin,

warfarin embryopathy, or 4i*ala

syndrome

• It occurs when warfarin 7or another

+-hydro2ycoumarin derivative8 is

given during the 5rst trimesterP

particularly between the si2th and

ninth weeks of pregnancy

• Associated conditions incl!de6

o &ypoplasia of nasal bridge

o laryngomalacia

o ectus carinatum

o #ongenital heart defects

o Ventriculomegaly

o 3genesis of the corpus

callosum

o "tippled epiphyses

• Associated with nasal hypoplasia and

chondrodysplasia in the %rst

trimester

• L* abnormalities in later pregnancy

• ?igh incicence of hemorrhagic

complications toward the end of

pregnancy

• Leonatal hemorrhage is diQcult to

prevent because of the immature

enymes in fetal liver and low stores

of vitamin

• Becent study doses )9mg had

signi%cantly more fetal complications

independent of the maternal ILB


11/17

di0erent from fetal warfarin syndrome!

&he most common congenital

abnormalities associated with warfarin

use in late pregnancy are central

nervous system disorders,

including spasticity, seiures, and eyedefects

o Telebrachydactyly

o 8rowth retardation

Anticoag!lants7eparin (U7 8 9M47) (%)• 5ast-acting anticoagulant with a high binding aQnity for antithrombin III

• Used in the prophyla2is and treatment of .&< and < associated with pregnancy, which brings very high mortality to the

women if left untreated

• *afe during pregnancy as it doesn=t cross the placenta

•

&he most signi%cant side e0ect is heparin-induced thrombocytopenia, in addition to elevation of aminotransferase,hyperkalemia, and osteoporosis in chronic use

• 4oes not cross the placenta but may cause maternal osteoporosis and ?I&

Cytoto:ic dr!gs Anticon+!lsants

• yclophosphamide 748 and

chlorambucil 748, are

teratogenic and

contraindicated in

pregnancy

• ;ethotre2ate 7F8 should be

discontinued at least 3

months prior to conception

and 5A 79mg8 given pre-

conceptually

• Aathioprine 748o urrent evidence

Class o"Medication

Category%

Category C Category D

Anticonvulsants ;agnesium sulfate


12/17


13/17

conception

Cardio+asc!lar dr!gs

Class o"Medication

Category % Category C Category D

ardiovasculardrugs

!ethylopa?ydrochlorothiaide

AcetaolamideCalcium"channelbloc#erslonidine4igo2in


14/17

Cardio+asc!lar dr!gs• If the treatment of hypertension

is reEuired before D: weeks,

!ethylopa 768 should be the

%rst drug of choice

• &here is concern for use of beta-blockers in the Dnd and 3rd

trimesters given reports of

intrauterine growth restrictions,

although labetalol has the most

safety data of the class

• alcium channel blockers mainly

used for severe pre-eclamptic

to2emia 7


15/17


16/17

#ran0!ili2ers 8 antidepressants

• In the United *tates, the 54A has categoried

'en2odia2epines into categories D or & due to

potential harm to the fetus, SSRIs into category C,

and 9ithi!m into D that is not commonly used• &heir use by e2pectant mothers shortly before the

delivery may result in a /oppy in"ant syndrome, with

the newborns su0ering

from hypotonia, hypothermia, lethargy, and breathing

and feeding diQculties

• ases of neonatal ;ithdra;al syndrome 7usually self-

limited8 have been described in infants chronically e2posed

to benodiaepines in utero

• If used in pregnancy, those benodiaepines with a betterand longer safety record, such

as iazepam or chloriazepoie, are recommended over

potentially more harmful benodiaepines, such

as alprazolam or triazolam

• Using the lowest e0ective dose for the shortest period of

time minimies the risks to the unborn child

Class o"medication

Category % Category C Category D Category &

Antidepressants<antipsychotics<an:iolytics

%!proprion%!spirone=olpidem

Aripipra2oleChlorproma2ineClo2apine7aloperidol$lan2apine>!etiapineRisperidone

SSRIs#CAs#hiorida2ine=iprasidone

Alpra2olamChlordia2epo:ideClona2epamDia2epam9ithi!m9ora2epamMida2olam$:a2epam

$ther %D=

%ronchial Asthma


17/17

• &reat as non-pregnant,

despite of the side e0ects of

drugs, as an asthma attack

7status asthmaticus8 can be

very serious to the mother

and baby• In general, respiratory drugs

are either into category 6 or

, and so are relatively safe

during pregnancy

Class o"Medication

Category % Category C

Respiratorydr!gs

Acetylcysteine

%!desonideCromolynsodi!mIpratropi!mMontel!kast=a5rl!kast

Al'!terolCorticosteroids (inhaled)

De:tromethorphanG!ai"enesinSalmeterol#heophylline

S!mmary

• &he decision to use any potentially harmful drug in pregnancy should be made on a case-by-case basis

• &here should be thorough counseling with the patient

Documents

Belle-drugs in Pregnancy