Drugs in pregnancyDrugs in pregnancy

Jiří Slíva, MD., Ph.D.

Risks of pharmacotherapy Risks of pharmacotherapy in pregnant womenin pregnant women administration of a contraindicated

drug

Non-use of an indicated drug

RealityReality

SmPC/PIL:

„the drug can be given only if the potential benefit for both mother and fetus outweighs the potential risks“

= ALIBISMS

Categories of risk – FDA

AA – controlled trials in pregnant women -levothyroxin,

liothironin, folic acid

BB – animal studie negative and controlled clinical trials not

available - paracetamol

CC - teratogenic in animals, no clinical trials or not available

in animals in women - teofylin, amlodipin

DD – there are known risks, but you can not substituten -

beta-blockers, ACEi (III. trimester)

XX – risks overweights the benefits oral contracetives, statins,

finasterid, isotretinoin, warfarin, misoprostol, androgens

Risk categoriesRisk categories

Australia (ADEC) - A, B 1-3, C, D, X A – proved as safe X – documented teratogens

Germany – grades 1.–11.

A teratogen is an agent that can

produce a permanent alteration of

structure or function in an organism

exposed during embyronic or fetal

life.

Teratogen is…

Multifactorial42 %

Unknown37 % Chromosomal

3 %

Monogenic8 %

Teratogens10 %

Baird et al., 1988

Birth Defects in Childhood

Teratogenicity influencing factors

Nature of the agent Dose Route Frequency of exposure Duration of exposure Time of exposure, i.e. gestational timing

Concurrent exposures Concurrent illness Genetic susceptibility

Teratogenic influence of Teratogenic influence of drugsdrugs „Timing“ of teratogenic impuls („window“)

before implantation – blastogenesisblastogenesis – low sensitivity

(„all or nothing“)

! 15.-55. day of gravidity – organogenesisorganogenesis – an

increased risk (1st trimester)

fetal periodfetal period – usually no visible malformations but for

example alteration of CNS functions

Birth Defects Caused Birth Defects Caused

By Teratogenic By Teratogenic

Exposures Are Exposures Are

Preventable.Preventable.

Prevention of known teratogenic exposures

Public Health Concerns

– Alcohol – Infectious diseases– Occupational exposures– Environmental exposures– Drugs abused– Medication– etc.

PlacentaPlacenta

lot of substances cause anomalies of the fetus

drugs cross the placenta usually via diffusion

minimal penetration is observed in highly dissociated or in

lipophobic substances

placenta is NOTNOT barrier protecting the fetus from drugs

administered to its mother

Fetal rubeolla Fetal rubeolla syndromesyndrome

Fetal aminopterine Fetal aminopterine syndromesyndrome

Fetal hydantoine syndromeFetal hydantoine syndrome

Fetal valproate syndromeFetal valproate syndrome

Fetal warfarin Fetal warfarin syndromesyndrome

Fetal alcoholic syndromeFetal alcoholic syndrome

Fetal hyperpyretic Fetal hyperpyretic syndromesyndrome

Over-the-counter medicines Herbals and dietary supplements Prescription drugs

Medications

Frequently used by pregnant women

Biologically active Taken systemically Taken in high doses Information about teratogenicity very limited

Teratogenic Risk of 468 Drugs Approved 1980–2000

0%

20%

40%

60%

80%

100%

0-4 5-9 10-14 15-20

Years Since FDA Approval

Undetermined None, Minimal or Unlikely Small, Moderate or High

Lo & Friedman et al., 2002

Teratogenic Risk of 468 Drugs Approved 1980-2000 11 (2.4 %) of treatments pose a “small”,

“moderate” or “high” teratogenic risk

On average, 6.0 ± 4.1 years after FDA approval required to recognize risk in humans

30 (6.4 %) of treatments unlikely to pose a risk in human pregnancy

On average, 9.1 ± 4.5 years after FDA approval required to show safety in humans

Lo & Friedman et al., 2002

AnimalAnimal teratology studies teratology studies are valuableare valuable

but but ……

false positivesfalse positives and and false negativesfalse negatives dodo

occur.occur.

Animal Teratology Studies: False Positives

corticosteroids

chlorpheniramine

hydroxyzine

propoxyphene

Animal Teratology Studies: False Negatives

ACE inhibitors: captopril, enalapril etc.etc.

Carbimazole, methimazole

Misoprostol

Lack of Knowledge Is a Problem

1. Exposures that really do pose a risk remain unrecognized

2. Pregnant women may not receive treatments that benefit their own health or that of the fetus

3. Labeling tends to provoke anxiety, often unnecessarily

4. Women may be advised or choose to terminate pregnancy to avoid risk

Thalidomide etc.Thalidomide etc.

not only thalidomide, but also lenalidomide or

pomalidomide are being introduced to haematooncologic

praxis (MM, myelodysplastic sy etc.)

inhibition of angiogenesis, hematopoesis,

immunomodulation

decreased synthesis of TNF-alpha and IL-6 monocytes,

stimulation of T cells & NK cells

Thalidomide etc.Thalidomide etc.

Chanan-Khan A, 2006

THALIDOMIDE

Thalidomide (Contergan) – 1956 – morning nausea of pregnant women in 28 countries 100 000 kg of thalidomide, malformed more than 10.000 children – phocomelie teratogenic dose in men very low ! (0,1 mg/kg) tested several animal species (except of rabbitt) – 20–300

mg/kg only one dose is sufficient 50-100 mg in critical period

(21.–36. after conception)

testing of newly developed testing of newly developed substances in pregnant substances in pregnant

women is women is unallowableunallowable

Mechanisms of Mechanisms of impairmentsimpairments

often non-specific often hardly recognisible

thalidomide – cca 25 of theories corticosteroids – clefts in animal but not in human

direct toxicity – cytostatics, antiep. (PHE, CBZ, VAL) placentar transport – Cd multifactorial

Instruments for Instruments for identification of identification of teratogenity in human teratogenity in human pharmacologypharmacology Case-reportsCase-reports – lithium – hearth malformations

Case-control studiesCase-control studies – stilbestrol – vaginal adenoca,

ASA in I. trimester (teratogenic in animals)

Cohort studies (prospective)Cohort studies (prospective) – fluoxetine

(Interventional studies)(Interventional studies) – RCT – folic acid (0.8 mg daily in

prevention of neural schisis)

Meta-analysesMeta-analyses – metronidazol etc.

Teratogens in the first trimester

phenytoin, carbamazepine, valproate – neural tube defects

(spina bifida)

lithium – cardiac malformations

warfarin – bone deformation, chondrodysplasy, CNS defects

heparin (demineralization of bone in mother –> switch to

LMWH)

retinoids - def. of CNS, heart, limbs, liver

oncologic drugs (fluorouracile, methotrexate,

cyclophosphamide, busulfan, …)

Teratogens in fetal period

ACEI – renal failure, oligohydramnion

thyreostatics (carbimazole, thiamazole, propylthiouracil)

benzodiazepins - dependency

barbiturates – dependency

beta-blockers (atenolol)

NSA – constriction of ductus

tetracyklins – disturbances of bone mass, teeth

warfarin – intracranial hemorhagies

aspirin - bleeding

cytostatics

ConclusionsConclusions

think of possible pregnancy when the drug is prescribed in every women in productive age

in chronicaly medicated patients (epilepsy, diabetes, hypertension) evaluate the medication so far administered

not suitable to disrupt the effective pharmacotherapy without careful balancing the risk/benefit ratio

…varia….

Asthma during pregnancyAsthma during pregnancy

global increase of prevalence during last two decades

the most common chronic disease during pregnancy

prevalence: 3.4–12.4 %

Rey, 2007

Physiologic changes durign Physiologic changes durign pregnancy regarding the effects pregnancy regarding the effects of anti-asthmatic drugsof anti-asthmatic drugs

increased concentration of free cortisol in plasma

(antiinflamm. eff.)

increased level of progesterone (bronchodilat. eff.)

increased synthesis of of potential bronchoconstrictors

(PGF 2 etc.)

Rey, 2007

Antiastmatics during Antiastmatics during pregnancy I.pregnancy I. corticosteroids p.o.corticosteroids p.o.

inactivation of prednisolone by placenta (up to 90 %) in 1st trimester higher risk of cleft palate or harelip (RR: 1.1–1.3

%) – benefit usually outweighs the potential risk

prospective, case-control study, systematic reviews => safety of the administration ofsafety of the administration of: ICSs (most of studies with budesonide) SABAs theophylline cromons => not increased risk of congenital abnormalities, pre-

eclampsia, preterm deliveries or small-for-date infants

in most cases no need to change the medication, including dose or frequency

Rey, 2007

Antiasthmatics during Antiasthmatics during pregnancy II.pregnancy II. beta-2 mimetics beta-2 mimetics

malformation in animals when high doses were used

no malformation in human; no increase of preterm deliveries or low

weight => recommendation of their combination with ICS

leucotriene receptors antagonistsleucotriene receptors antagonists zafirlukast – 0 teratogenity in animals; lack of studies in human =>

recommendation of ICS

montelukast – 0 malformation or ADRs associated with pregnancy,

but commonly not use

Rey, 2007