Clinical Pregnancy Pregnancy & Lactation

8/17/2019 Clinical Pregnancy Pregnancy & Lactation

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Clinical Pharmacy

(Chapter 1)

Drug Use in Pregnancy &

Lactation


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FDA Pregnancy Categories for Medication Use

A Controlled studies in pregnancy (


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FDA Pregnancy Categories for Medication Use ## continue

C $uman data lac!ing" animal studies positie or not done (&&%)

Animal studies have sho'n an adverse effect on the fetus and there areno adequate studies in humans$ or no studies are availale in either

animals or 'omen! Potential enefits may 'arrant its use! ,pinephrine$

phenylpropanolamine$ trimethoen-amide$ aspirin$ atropine$

prometha-ine$ theophylline$ lisinopril$ potassium chloride$ disulfiram$

acyclovir$ propranolol

D $uman data sho ris!" 'enefit may outeigh

Positive evidence of human fetal risk ased on adverse reaction data$ ut

potential enefits in serious situations may 'arrant its use! .arfarin$

tetracycline$ phenytoin$ dia-epam$ trimethadione$ lora-epam$ amitriptyline

/ Animal or human data positie" no 'enefit

*tudies in animals or humans have demonstrated fetal anormalities

and0or there is positive evidence of human fetal risk$ and the risks clearly

out'eigh any potential enefits! +sotretinoin$ diethylstilestrol$

phencyclidine (P%P)$ tria-olam$ /rays$ chemotherapy


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Prealence of diseases during pregnancy

Complication Prealence Medication

,pilepsy 12334 Phenytoin (D)

Depression 15634 7luo#etin (**8+) (D)$"%As (cause irthdefects)

8A (Prolactin proinflammator)

prevalence of 8A is 59 timeshigher in female than male

%orticosteroids (%)$+mmunosuppressives$

*A+Ds

:ypertension 14 in pregnancyPreeclampsia 6+ complication ausea$ vomiting and

dyspepsia in 9?4

8anitidine ()$

@mepra-ole (%)+D Ulcerative colitis proceed in

64 'omen=tronida-ole$ %ipro

U"+ Baginal +nfection 394%ystitis 54Pyelonephritis 6934

@ral Antiiotics


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Critical periods in human fetal deelopment (prenatal deelopment)

"he human gestation period is appro#imately 5 'eeks from the first day of the last

menstrual period (3< 'eeksC post conception) and is conventionally divided into the first$

second and third trimesters$ each lasting 3 calendar months! Another method for

classifying the stage of pregnancy is according to the stage of fetal development! "his is a

more useful approach 'hen assessing the potential risks associated 'ith drug use in

pregnancy!

Preem'ryonic stage (ee!s *+ postconception, 1-days)

"he first t'o 'eeks postconception are regarded as the preemryonic stage and descrie

the period up to implantation of the fertili-ed ovum!

.m'ryonic stage (ee!s /0 postconception, 1-days to & days)

@rganogenesis occurs predominantly during the emryonic stage and$ 'ith the e#ception

of the central nervous system$ eyes$ teeth$ e#ternal genitalia and ears$ is complete y the

end of the 1th 'eek of pregnancy! ,#posure to drugs during this critical period therefore

represents the greatest risk of maor irth defects! 7or this reason$ 'omen are often

advised to avoid or minimise all drug use in the first trimester 'henever possile!

Fetal stage (ee!s 2*/0 postconception)

During the fetal stage$ the fetus continues to develop$ gro' and mature and$ importantly$

remains susceptile to some drug effects! "his is especially true for the central nervous

system$ 'hich can e damaged y e#posure to certain drugs$ for e#ample$ ethanol$ at any

stage of pregnancy!


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D.345.67

*ome drugs given late in pregnancy or during delivery may cause particular

prolems! Pethidine$ administered as an analgesic can cause fetal apnoea

('hich is reversed 'ith nalo#one)! Anaesthetic agents given during %aesarean

section may transiently depress neurological$ respiratory and muscular functions!.arfarin given in late pregnancy causes a haemostasis defect in the ay$ and

predisposes to cereral haemorrhage during delivery!

8$. MA3.

Although it is generally considered that sperm cells damaged y drugs 'ill not

result in fertili-ation$ the manufacturers of griseofulvin$ an antifungal agent$

advise men not to father children during or for si# months after treatment!

7inasteride$ an antiandrogen used in the treatment of enign prostatic

hyperplasia$ is secreted in semen$ and may e teratogenic to male fetuses!

Drug dose during pregnancy

A threshold dose aove 'hich druginduced malformations are more likely to

occur has no' een demonstrated for certain teratogenic compounds$ although

for most a Esafe doseF has not een conclusively determined! "he likelihood of a

dose relationship underlies the recommendation to use the lo'est effective dose

in pregnancy! 7or this reason$ more frequent monitoring of drug levels may e

recommended for certain drugs during pregnancy!


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Drugs as teratogens

A teratogen is defined as any agent that results in structural or functional anormalities in

the fetus$ or in the child after irth$ as a consequence of maternal e#posure during

pregnancy!

Dysmorphogenesis is structural or functional irth defects$ literally means an illshaped or

malformed ody structure!

%ongenital anomalies are also kno'n as irth defects$ congenital disorders or congenital

malformations! %ongenital anomalies can e defined as structural or functional non

reversile anomalies that occur during intrauterine life and can e identified prenatally$ atirth or later in life$ caused y genetic predisposition (defective gene 'as latent ut started

multiplication y stimulation) or drug e#posure that adversely affect fetus development! "'o

types of anomalies found$ immediate and delayed !

%auses of anomalies include socioeconomic and demographic factors (aout ?54 of

severe congenital anomalies occur in lo' and middleincome countries$ 'here 'omen

often lack access to sufficient$ nutritious food and may have increased e#posure); >eneticfactors$ infection during pregnancy (syphilis and ruella); =aternal nutritional status (+odine

deficiency$ folate insufficiency$ oesity and diaetes mellitus) ; ,nvironmental factors

(certain medications$ alcohol$ toacco$ psychoactive drugs and radiation during

pregnancy)!


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Drugs as teratogens #9

continues

External (immediate) congenitalanomalies such as lim

anormalities$ spina ifida

(spinal cord defective closure)

and hydrocephalus (enlarged

skull due to lockade of %*7

path'ay) may e ovious at

irth$ some defects may takemany years to manifest

clinically or e identified!

,#amples of delayed effects of

teratogens are the ehavioural

and intellectual disorders

associated 'ith in utero alcohol

exposure and the development

of clear-cell vaginal cancer in

young 'omen follo'ing

maternal intake of

diethylstiloestrol$ for the

prevention of miscarriage and

preterm delivery!


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D

r u g

e f f e c t s o

n f e t u

s


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A9 Placental 8ransfer of drugs

G +n the placenta$ maternal lood is separated from fetal lood y a cellular

memrane! =ost L=. drugs 'ith a molecular 'eight of less than 1 can cross

the placenta! "his is usually y passive diffusion do'n the concentration gradient$ut can involve active transport! :o'ever$ L=. drugs have limited transfer eg!

:eparin!G "he rate of diffusion depends first on the concentration of free drug (i!e! non

protein ound) on each side of the memrane$ and second on the lipid soluility of

the drug$ 'hich is determined in part y the degree of ioni-ation! Diffusion occurs

if the drug is in the unioni-ed state!G .eakly asic drugs entrapped in fetal circulation due to lo'er p: than maternal

plasma!G *ome drugs are metaoli-ed y the fetus0plasmaG Placental function is also modified y changes in lood flo'! "his may e the

mechanism 'hich causes the small reduction in irth 'eight follo'ing treatment of

the mother 'ith atenolol in pregnancy!G @ccasional drug delivery is to treat fetal disorders! ,g! 7lecainide is given to

resolve fetal tachycardiaG "he fetal is not developed until the second half of pregnancy$ and the

susceptiility of the central nervous system (%*) to developmental to#ins may

e partly related to this! "he human placenta possesses multiple en-ymes that

are primarily involved 'ith endogenous steroid metaolism$ ut 'hich may also

contriute to drug metaolism and clearance!


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7etal and ne'orn plasma proteins appear to ind ampicillin and en-ylpenicillin 'ith

less affinity and salicylates 'ith greater affinity$ than maternal proteins! =aternal

alumin gradually decreases during pregnancy and fetal alumin concentrations

increase$ so different fetalH maternal alumin concentrations occur at different stages

of pregnancy! "he degree of protein inding of any drug is an important determinantof its movement across the placenta! Drugs 'hich are highly protein ound tend to

achieve higher maternal and lo'er fetal concentrations!

:9 Pharmacological effects

Pharmacological effects are usually dose related and to some e#tent predictale!Drugs may adversely affect the fetus via effects on the maternal circulation or they

may cross the placenta and e#ert a direct pharmacological effect on the fetus!G%orticosteroids in high doses (eg! Prednisolone more than 1mg daily) causes fetal

renal suppression i! e! reduce aI reasorption and JI0:I secretion!G=aternal treatment 'ith anti hypertensive drugs cause fetal hypo#ia secondary to

maternal hypertension!G"he capacity of the neonate to eliminate drugs is reduced$ and this can result in

significant accumulation of some drugs$ leading to to#icity! eonatal 'ithdra'al may

require treatment!G+f a pregnant 'oman takes paro#etine$ echocardiography should e done to evaluate

the fetusCs heart ecause paro#etine appears to e associated 'ith an increased

incidence of congenital cardiac anomalies!


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C9 4diosyncratic effects

+diosyncratic drug effects in the fetus and neonate are possile ut occur rarely

compared 'ith pharmacological effects! *ome effects of drugs are less

predictale and unrelated to dose! "hese idiosyncratic effects are caused yK

G 7etal genetic predisposition (defective gene comple#ity)GUnkno'n threshold dose for individual 'hich leads to dysmorphogenecity!

+diosyncratic drug effects leads to maor irreversile congenital anomaly so lo'er

effective doses are suggested!

D9 8iming of drug e;posure

"he stage of pregnancy at 'hich a drug e#posure occurs is key to determining

the likelihood$ severity or nature of any adverse effect on the fetus! 8isk oth

et'een and 'ithin trimesters may e variale!

7or e#ample$ folic acid antagonists$ for e#ample$ trimethoprim$ are associated

'ith an increased risk of neural tue defects if e#posure occurs efore neural

tue closure (third to fourth 'eek postconception)$ ut not after this period! +t

has also een suggested that trimethoprim should e avoided after 36 'eeksC

gestation in vie' of the theoretical risk of severe aundice in the neonate as a

result of iliruin displacement from protein inding!


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8iming of drug e;posure ## continues

Phenoarital cause congenital anomaly in 1st trimester and cause neonatal

leeding if given in 3rd trimester! .omen 'ho are taking more than one drug for

sei-ure control$ Phenoarital also e#erts 'ithdra'al effects in the ay! ,#posure

in any trimester may e due to the fact that it reduces the efficiency of irth control

pills!

"he e#ternal genitalia also continue to form from the seventh 'eek until term$ and

consequently$ dana-ol (#)$ 'hich has 'eak androgenic properties used to treatendometrosis and firocytic reast disease! +f therapy is intiated during

menstruation$ test should e performed and nonhormonal cotraceptive should e

performed! +t may cause virilisation of a female fetus if given in any trimester after

the eighth 'eek of pregnancy ('hen the androgen receptors egin to form)!

%onversely$ due to anti androgenic property spiranolactone and cyproteroneacetate cause femini-ation of male fetus! .omen take them to counteract male

hormones (testosterone) on skin! ut it is not suitale for men skin! "hey are

cominely used to skip menstruation and pregnancy$ treatment not necessary for

post menopausal 'omen!


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8iming of drug e;posure ## continues

Drugs that interfere 'ith this process can cause gross structural defects if given

during organogenesis (e!g! thalidomide phocomelia)! "halidomide 'as unusual

in the 'ay in 'hich a very small dose predictaly produced seriousmalformations!

"he nonsteroidal antiinflammatory drugs (*A+Ds) are another important group

of drugs that may cause prolems specifically in the third trimester! "hese drugs

inhiit prostaglandin synthesis in a doserelated fashion and$ 'hen given late in

pregnancy$ may result in premature closure of the fetal ductus arteriosus$

leeding disorder$ delayed purturition and fetal renal impairment! *A+Ds should

therefore e avoided during the third trimester!

Diethylstilestrol$ an association 'as reported et'een adenocarcinoma of the

vagina in girls in their late teens 'hose mothers had een given diethylstilestrol

during the pregnancy! ,#posure to stilestrol in utero has also een increased

rates of ectopic pregnancy and premature laor!

*ulphonamides and thia-ides at 3rd trimester cause neonatal hemolysis and

thromocytopenia respectively!


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7urther e#amples include the angiotensinconverting en-yme (A%,) inhiitors$ 'hich

if given in the second and third trimesters can result in fetal renal dysfunction and

susequent oligohydramnios$ that is$ reduced amniotic fluid volume!

+n fetogenic stage

G Drugs used to treat maternal hyperthyroidism can cause fetal and neonatal

hypothyroidism!

G "etracycline antiiotics inhiit gro'th of fetal ones and stain teeth!

G Aminoglycosides cause fetal


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.9 Drug dosing during pregnancy

Drug dose should e tapered to the lo'est effective dose either efore

conception or during 1st trimester! ,g! Doses of antipsychotic and

antidepressants should e reduced as the term approaches cause they have

potential to cause neonatal 'ithdra'al effects! ut some pharmacokineticchanges may demand dose increase! Pregnancy itself can cause a temporary

'orsening or improvement of some diseases and in that 'ay influence drug

dosages!

Maternal pharmaco!inetic changes

A9 A'sorption

>astric and intestinal emptying time increases y 3M54 in the second and

third trimesters and could e important in delaying asorption and time to onset

of action for some drugs! "here is also a reduction in gastric acid secretion in

the first and second trimesters and an increase in mucus secretion! As a

consequence of the increase in gastric p:$ the ioni-ation$ and hence asorption$

of 'eak acids and ases can e affected! %ardiac output and respiratory volume

increase during pregnancy leading to hyperventilation and increased pulmonary

lood perfusion! "hese changes cause higher pulmonary asorption of

anesthetics$ ronchodilators$ pollutants$ cigarette smoke and other volatile

drugs!


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Maternal pharmaco!inetic changes #9

:9 Clearance

.ithin the first fe' 'eeks of pregnancy$ the glomerular filtration rate (>78)increases y appro#imately 94 'ithin 1st fe' 'eeks of pregnancy and remain

raised until after delivery! %onsequently$ those drugs 'hich are e#creted

primarily unchanged y the kidneys$ for e#ample$ lithium$ digo#in and penicillin$

sho' enhanced elimination and lo'er steadystate concentrations! Lithium and

antiiotics dose should e increased ecause of their unchanged clearance! "he

follo'ing drugs have sho'n pregnancyinduced increases of 6M94 on theirrenal eliminationH

G Ampicillin$ %efuro#ime$ %efta-idime$ %efa-olin$ Pipericillin$ Atenolol$ *otalol$

Digo#in$ Lithium$ Dalteparin sodium$ ,no#aparin sodium

:epatic clearance of many drugs increased during pregnancy possily due to

en-yme induction y endogenous progesterone! 7or this increased metaolism

of methadone and phenytoin requires higher maintenance dose! %onversely

theophylline metaolism decrease so revised reduced maintenance dose is

required!


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C9 5olume of distri'ution

"he volume of distriution of drugs may e altered ecause of an increase of upto 94 in lood (plasma) volume and a 34 increase in cardiac output! 8enal

lood flo' increases y up to 94 at the end of the first trimester and uterine

lood flo' increases and peaks at term (3M56 L0h)! "here is also a mean

increase of < L in ody 'ater (4 to placenta$ fetus and amniotic fluid and 54

to maternal tissues)! As a consequence$ there may e increased dosage

requirements for some drugs to achieve the same therapeutic effect$ providedthese effects are not offset y other pharmacokinetic changes! oth the total

plasma and the freedrug concentrations of phenytoin$ carama-epine and

valproic acid decrease during pregnancy$ ut the freedrug fraction (ratio of free

to total plasma concentration) may increase!


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D9 Protein :inding

Alumin is the main plasma protein responsile for inding acidic drugs such as

phenytoin and salicylates$ 'hilst N1acid glycoprotein predominantly inds asic

drugs$ including Olockers and opioid analgesics! As pregnancy progresses$ the

plasma volume increases at a greater rate than the increase in alumin 'hich

results in hypoaluminaemia! +n addition$ steroid and placental hormones

occupy the protein inding sites! "his leads to an increase in the fraction ofunound drug! %linical effect is related to the concentration of unound drug$

'hich usually remains unchanged even though the total (ound plus unound)

plasma concentration is decreased! "hus$ a fall in the total plasma concentration

does not usually require an increase in dose! "he N1acid glycoprotein

concentrations remain the same as those in nonpregnancy!

Phenytoin is ound to alumin and e#hiits the effects descried earlier$ ut the

situation is further complicated y increased hepatic metaolism that may

necessitate a dose increase!


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.ffects of drugs on neonates

%apacity of drug elimination is minimal in fetus or neonate 'hich results

significant drug accumulation and to#icity! *o at the end stage drug dose shoulde lo' as possile!

Dose of antidepressants or neuroleptics should e slo'ly reduced close to

purturition to minimi-e neurological disturance (to#icity) and to minimi-e

'ithdra'al effects! "his is very much distressing and symptoms often require

sedative treatment! =orphine oral solution is used to 'ean ay off methadone

"apering of the dose is not al'ays practical for methadone and lithium 'hich

actually need to increase to maintain symptom control of mother!


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Drugs in lactation

reast milk is the est form of nutrition for young infants! +t provides all the

energy and nutrients required for the first months of life! "he .:@ andU+%,7 recommend e#clusive reastfeeding for this period! enefits of

reastfeeding include protection of the infant against gastric$ respiratory and

urinary tract infections and reduction in rates of oesity uvenileonset

diaetes and atopic disease ! Adults 'ho 'ere reastfed as infants often have

lo'er lood pressure and lo'er cholesterol levels! =aternal enefits include

reduced risk of developing premenopausal reast cancer and delayedresumption of menstrual cycle! reastfeeding also strengthens the motherM

infant ond!

Drugs that affect dopamine activity are the main cause of effects on milk

production$ mainly mediated y effects on prolactin! ,arly postpartum use of

oestrogens may reduce the volume of milk$ ut the effect is variale and

depends on the dose and the individual response! Progestogen

contraceptives are preferred!

Drugs may occasionally e used therapeutically for their effect on lactation!

Dopamine agonists such as caergoline decrease milk production!


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Drugs in lactation

reast milk is the est form of nutrition for young infants! +t provides all the

energy and nutrients required for the first months of life! "he .:@ andU+%,7 recommend e#clusive reastfeeding for this period! enefits of

reastfeeding include protection of the infant against gastric$ respiratory and

urinary tract infections and reduction in rates of oesity uvenileonset

diaetes and atopic disease ! Adults 'ho 'ere reastfed as infants often have

lo'er lood pressure and lo'er cholesterol levels! =aternal enefits include

reduced risk of developing premenopausal reast cancer and delayedresumption of menstrual cycle! reastfeeding also strengthens the motherM

infant ond!

Drugs that affect dopamine activity are the main cause of effects on milk

production$ mainly mediated y effects on prolactin! ,arly postpartum use of

oestrogens may reduce the volume of milk$ ut the effect is variale and

depends on the dose and the individual response! Progestogen

contraceptives are preferred!

Drugs may occasionally e used therapeutically for their effect on lactation!

Dopamine agonists such as caergoline decrease milk production!


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Preconception adice

,pilepsy is an e#ample$ in 'hich$ if continued drug treatment is necessary$

attempts are made to stailise treatment 'ith a single drug at the lo'est effective

dose! +t is also important to note that many pregnant 'omen ecomeless adherent to their drug therapy out of concern aout possile harm to their

infant! +n many cases$ such as asthma$ inflammatory o'el disease$ epilepsy$

inadequate treatment of the underlying disease may e more detrimental to the

motherMfetus pair than the drugs used to treat the condition!

All 'omen planning a pregnancy should e offered general advice to minimise therisk of congenital anomalies! "his includes avoidance of recreational drugs$

EnaturalF or heral remedies$ alcohol$ smoking$ vitamin A products$ minimisation of

caffeine consumption and eginning daily supplementation 'ith at least 5 cg of

folic acid to reduce the risk of neural tue defects! +t is recommended that the daily

dose of folic acid e increased to around 5M9 mg daily in 'omen 'ho have

epilepsy or 'ho have had a previous child 'ith a neural tue defect! *omeinfectious diseases may carry important fetal consequences if contracted during

pregnancy! 7or e#ample$ ruella infection in the first 6 'eeks of pregnancy is

associated 'ith an increased risk of miscarriage and a syndrome comprising

prolems such as deafness$ cardiac defects and mental retardation in more than

64 of pregnancies!


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Postconception adice

+t is important to dra' distinction et'een advice given to 'omen pre

conceptually and that provided to a pregnant 'oman 'ho has already eene#posed to a drug! +n the former setting$ it may e recommended that an

alternative preparation e considered or that a drug treatment e stopped

'here clinically appropriate! "his advice often hinges on the lack of definitive

safety data and does not automatically translate to e#posure to that drug in

pregnancy eing an indication for discontinuing the drug$ additional fetal

monitoring or termination of the pregnancy on the asis of the e#posure! Anychange to the 'omanCs medication should e ased on a careful and

individual risk assessment and include a discussion 'ith the 'oman to

provide her 'ith accurate uptodate evidence ased advice! +n many such

cases$ the 'oman can e reassured that a normal ay is the most likely

outcome$ or 'here appropriate e offered additional prenatal investigation to

screen for congenital malformation 'here the risk to fetus is considered to esignificant!


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%ase 1!

A 'oman is 'eeksC pregnant and has een diagnosed 'ith

depression that 'arrants pharmacological intervention! *he

'ishes to recommence venlafa#ine$ 'hich has een helpful in the

past! *he is also an#ious that the ethanol she consumed around

the time of conception may have harmed her ay!

Questions

1! .hat are the safest antidepressants in the first trimester

of pregnancyR

6! +s it reasonale for her to commence venlafa#ineR

3! +s there any risk from the ethanol ingestionR

Case Presention


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.hat are the safest antidepressants in the first trimester

of pregnancyR

"ricyclic antidepressants ("%As) have een e#tensively used in

pregnancy and are generally regarded as safe! 7or this reason$

past practice 'as to recommend that "%As should e used

preferentially for the treatment of depression in pregnancy 'hen

considering teratogenic risk to the fetus! "%As are$ ho'ever$

associated 'ith side effects including risk of maternal

cardioto#icity$ particularly in overdose! 7urther$ availale data on

"%A use in pregnancy do not prove that they are less teratogenic

than other antidepressant classes such as * 8+s and ** 8+s!

An antidepressant other than "%As may therefore e appropriate foruse in pregnancy$ and the risks and enefits for each should e

considered and ideally discussed 'ith the patient on a casey

case asis!


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4s it reasona'le for her to commence enlafa;ine

,#perience 'ith the use of venlafa#ine and many other antidepressants$ for

e#ample$ mocloemide$ in pregnancy is limited! :o'ever$ in some

instances$ it may e necessary to use an agent such as venlafa#ine! 7or

e#ample$ if the mother had a history of severe depression that did notrespond to multiple trials of other antidepressants$ then venlafa#ine may

e considered the most appropriate choice of antidepressant for that

'oman! + n this case$ any potential risks associated 'ith venlafa#ine are

likely to e less than those associated 'ith inadequately treated

depression!

4s there any ris! from the ethanol ingestion

,thanol is a human teratogen! 7etal alcohol spectrum disorders are

characterised y lo' irth 'eight$ facial dysmorphogenesis and delayed

development! A Esafe limitF for alcohol consumption in pregnancy has not

een defined$ and it is possile that very lo' amounts of alcohol mayproduce sutle effects on the fetus! "herefore$ the est practice is to avoid

all alcohol e#posure in pregnancy! + n this case$ the mother ingested

ethanol at the time of conception! * he should e reassured that this is

regarded as a relatively safe period and is not e#pected to adversely affect

the fetus ! :o'ever$ further ethanol ingestion should e avoided!


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%ase 6!

A 3yearold 'oman 'ith epilepsy is currently taking valproic acid

19 mg daily! *he 'ishes to conceive ut is concerned aout the

possiility of irth defects due to valproate e#posure in pregnancy!

:er sei-ures have een difficult to control 'ith alternative

anticonvulsants!

Questions

1! .hat are the risks associated 'ith valproate treatment in

pregnancyR

6! :o' can these risks e minimisedR


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.hat are the risks associated 'ith valproate treatment in

pregnancyR

Balproate is a human teratogen$ 'ith early firsttrimester e#posure

associated 'ith a 1M64 risk of neural tue defects$ as 'ell as

other malformations such as orofacial clefts! Balproate has also

een associated 'ith neonatal complications such as sei-ures! + tis frequently advised that valproate is avoided in pregnancy and

that the valproate dose should e gradually tapered and

discontinued prior to conception! :o'ever$ this is not a realistic

option for many 'omen 'ith epilepsy! + n fact$ sei-ures may lead

to greater prolems such as maternalMfetal inury$ miscarriage or

hypo#ia!


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:o' can these risks e minimisedR

"he patient should e reassured that most pregnancies in 'omen 'ith epilepsy

end 'ith a healthy ay 'ithout malformations! %oncern aout the risk of

fetal anormalities may result in reduced adherence$ 'hich may have

greater maternalMfetal risk than the drug itself! As the patient is not yet

pregnant$ this is an optimal time for her current drug regime to e revie'ed

and optimised y a neurologist or health professional 'ith e#pertise in

managing 'omen 'ith epilepsy during pregnancy! "here is some evidence

to suggest that higher doses0concentrations of valproate are associated 'ith

greater risk of malformations! .here valproate remains the drug of choice$

the lo'est effective dose should e used throughout pregnancy! =onitoring

free valproate concentrations may e useful in pregnancy$ perhaps 'ith the

vie' to maintaining those concentrations sho'n to e effective in the non

pregnant stage! :o'ever$ doses should e adusted ased on clinical needand not concentrations alone! .omen 'ith epilepsy should e commenced

on highdose folic acid 5M9 mg daily preconceptually! "hey should also e

offered the option of prenatal diagnostic techniques that screen for neural

tue defects such as ultrasound and serum Nfetoprotein!!


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%ase 3!

A 6dayold fullterm infant has e#cessive shrill crying$ is ittery

is feeding poorly! "he medical team cannot find any cause for theseeffects! "he mother is 'orried that they may e due to paro#etine

e#posure via reast milk and 'onders 'hether *t SohnCs 'ort 'ould e

a safer alternative! *he has taken paro#etine 6 mg daily throughout

pregnancy$ and this has een continued after delivery!

Tou note from a specialist te#took that the likely infant

e#posure is aout 64 of the 'eightadusted maternal dose!

Questions

1! .hat is the most likely drugrelated e#planationR

6! +s it safe for the mother to continue to take paro#etine 'hilst

reastfeedingR

3! +s * t SohnCs 'ort a reasonale alternativeR


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.hat is the most likely drugrelated e#planationR

"he most likely e#planation is a neonatal 'ithdra'al syndrome from

** 8+ use near term! * ymptoms typically occur 16 hM9 days after

irth! "he adult halflife of paro#etine is aout 65 h$ ut this is

much longer in a neonate! "here 'ill e a gradual decline in

paro#etine plasma levels in the neonate after delivery! Drug

e#posure in pregnancy is much greater than e#posure via milk!

"here may e some overlap of symptoms resulting from drug

transfer into reast milk and from in utero exposure – agitation,

itteriness$ hypotonia and gastrointestinal symptoms! :o'ever$

sedation has only een reported after drug e#posure via reast

milk! Paro#etine is one of the preferred ** 8+s in reastfeeding as

the halflife is shorter than most memers of the group and the

incidence of reported adverse effects is lo'!


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+s it safe for the mother to continue to take paro#etine 'hilst

reastfeedingR

"he mother should e reassured that the effects are not due to thetransfer of e#cessive amounts of paro#etine into milk! .ithdra'al

symptoms usually settle after a fe' days$ 'hereas adverse effects

due to the drug via milk 'ill remain 'ith continued e#posure! +f

symptoms persist$ further medical advice should e sought!

+s * t SohnCs 'ort a reasonale alternativeR

:eral remedies are often perceived as safe as they are natural!

+n general$ there is a lack of data to support the safe use of heral

remedies in lactation$ and their use should e avoided! +f a

pharmacological treatment is indicated$ then a drug for 'hich data

in lactation is availale$ for e#ample$ paro#etine should e used!


37/40

%ase 5!

A 6yearold female medical student attended her >P requesting a course of *eptrin

(cotrimo#a-ole) for cystitis! *he tells her >P that her last menstrual leed 'as

aout si# 'eeks earlier! *he did not think she 'as at risk of pregnancy as her

periods had een irregular since stopping the oral contraceptive one year previously

due to fears aout thromosis$ and her oyfriend used a condom! Physical

e#amination$ 'hich did not include a vaginal e#amination$ 'as normal! Urinalysis

'as 1 positive for lood and a trace of protein!

Question

=hy should the >P not prescri'e cotrimo;a?ole for this patient

Answer. Until proven other'ise$ it should e assumed that this 'oman is pregnant! %otrimo#a-ole (a comination of sulfametho#a-ole and trimethoprim) has een

superseded y trimethoprim alone as a useful drug in lo'er urinary tract infection

(U"+)! "he sulfametho#a-ole does not add significant antiacterial advantage in

lo'er U"+$ ut does have sulphonamideassociated side effects$ including the rare

ut lifethreatening *tevensMSohnson syndrome! oth sulfametho#a-ole and

trimethoprim inhiit folate synthesis and are theoretical teratogens! +f pregnancy is

confirmed (urinary frequency is an early symptom of pregnancy in some 'omen$due to a progesterone effect) and if the patient has a lo'er U"+ confirmed y pyuria

and acteria on microscopy 'hilst a'aiting culture and sensitivity results$ amo#icillin

is the treatment of choice! Alternatives include an oral cephalosporin or

nitrofurantoin! ote that lo'er urinary tract infection in pregnancy can rapidly

progress to acute pyelonephritis


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%ase 9!

A reastfeeding mother returned to see her mid'ife 5 'eeks after delivery of a fullterm

healthy infant! *he is complaining of ilateral nipple pain during and after

reastfeeding$ a prolem that 'as constant for the past 5 days! *he 'as advised to

use micona-ole cream 64 to the nipples after each feed! "his provided initial relief

ut symptoms returned after a fe' days! *he 'as given a course of flucona-ole 6mg daily for 15 days for a presumed candidal infection ut e#pressed concern that the

medication might affect the infant!!

Question

4s this regimen safe to use in lactation

Ans. "opical micona-ole is effective in treating superficial candidal infections$ ut oral

therapy 'ith flucona-ole is needed 'hen the infection spreads to the milk ducts! Assuming a mean flucona-ole milk level of 6!3 mg0L$ an infant 'eight of 5 kg and a

milk intake of 19 mL0kg0dayH "he estimated daily infant intake via milk 'ill e 6!3 V

!19 V 5 W 1!3< mg or !359 mg0kg0day! "his represents 1!394 of the 'eight

adusted dose for a kg 'oman taking 6 mg of flucona-ole daily and 9!294 of the

paediatric dose of mg0kg0day! "he mother may e reassured that the amount of

drug reaching the infant via milk is only a small fraction of the dose that 'ould eused to treat an infection in the infant!

=hat other therapeutic measures should 'e ta!en

Ans! %andidal infections are easily passed et'een the mother and the infant$ and oth

should receive treatment! +nfants can e treated 'ith nystatin suspension or oral

micona-ole gel! "he latter is not suitale for young infants under 5 months ecause of

the risk of choking on the viscous formulation$ and care is still needed 'ith older

infants


39/40

%ase !

A mother 'ho 'ishes to give up smoking seeks advice on the safety of nicotine

replacement therapy (8") 'hilst reastfeeding! *he is currently in the latter stages

of pregnancy ut does not 'ish to use these products until after delivery and has not

een successful in significantly reducing her smoking 'ithout aids!

Question

1! .hat effect is smoking likely to have on reastfeedingR

Ans. .omen 'ho smoke during pregnancy are less likely to reastfeed and more likely to

'ean their infants earlier! icotine reduces asal prolactin levels 'hich may lead to a

decrease in milk supply! + t also causes adrenaline release 'hich may inhiit the

release of o#ytocin and affect the milk letdo'n refle#! "oacco smoke may produce

reathing difficulties and other prolems in infants! =aternal smoking is a maor factorfor sudden infant death syndrome (*+ D*) and reastfeeding provides significant

protection!

+9 %an 8" e used safely 'hilst reastfeedingR

Ans! +deally$ reastfeeding mothers should stop smoking$ preferaly y using non

pharmacological methods! + f this is not possile$ most authorities advise that theamount of nicotine passing into milk after use of 8" is very much smaller than that

after smoking and less harmful than the secondhand smoke an infant might reathe

if the mother continues to smoke! 8" products are devoid of tars$ caron mono#ide

and respiratory irritants found in cigarettes! .here the infant has reathing difficulties$

8" should e avoided! @ther memers of the household 'ho smoke should also e

encouraged to give up smoking!


40/40

Question

3! +f so$ 'hich products are preferredR

Ans. .omen 'ho smoke during pregnancy are less likely to reastfeed andmore likely to 'ean their infants earlier! icotine reduces asal prolactin levels

'hich may lead to a decrease in milk supply! + t also causes adrenaline release

'hich may inhiit the release of o#ytocin and affect the milk letdo'n refle#!

"oacco smoke may produce reathing difficulties and other prolems in infants!

=aternal smoking is a maor factor for sudden infant death syndrome (*+ D*)

and reastfeeding provides significant protectionreast milk levels of nicotineafter use of a 61mg transdermal patch are roughly equivalent to smoking 12

cigarettes a day! =aternal plasma levels of nicotine after using a nicotine spray

are aout onethird those of smokers and levels after using

a gum are variale ut can e similar to those seen after smoking! + f possile$

nicotine patches should e avoided during reastfeeding ecause they provide a

continuous (ut lo') passage of nicotine into reast milk! +f patches are used$they should e removed at night time to decrease nocturnal e#posure! 7or

shorteracting preparations (e!g! gums$ lo-enges)$ it is est to reastfeed

immediately efore use and allo' a 6M3 hour period efore resumption of

reastfeeding to minimise infant e#posure!!

Clinical Pregnancy Pregnancy & Lactation

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