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