Download TERATOGENITY of DRUGS

Drugs in pregnancy
Jiří Slíva, MD., Ph.D.
Risks of pharmacotherapy in
pregnant women

administration of a contraindicated
drug

Non-use of an indicated drug
Reality

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

A – controlled trials in pregnant women -levothyroxin,
liothironin, folic acid

B – animal studie negative and controlled clinical trials
not available - paracetamol

C - teratogenic in animals, no clinical trials or not
available in animals in women - teofylin, amlodipin

D – there are known risks, but you can not substituten beta-blockers, ACEi (III. trimester)

X – risks overweights the benefits oral contracetives,
statins, finasterid, isotretinoin, warfarin, misoprostol,
androgens
Risk categories

Australia (ADEC) - A, B 1-3, C, D, X



A – proved as safe
X – documented teratogens
Germany – grades 1.–11.
Teratogen is…
A teratogen is an agent that can
produce a permanent alteration of
structure or function in an organism
exposed during embyronic or fetal
life.
Birth Defects in Childhood
Teratogens
10 %
Multifactorial
42 %
Monogenic
8%
Unknown
37 %
Chromosomal
3%
Baird et al., 1988
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 drugs

„Timing“ of teratogenic impuls („window“)

before implantation – blastogenesis – low sensitivity
(„all or nothing“)

! 15.-55. day of gravidity – organogenesis – an
increased risk (1st trimester)

fetal period – usually no visible malformations but for
example alteration of CNS functions
Birth Defects Caused
By Teratogenic
Exposures Are
Preventable.
Public Health Concerns

Prevention of known teratogenic
exposures
– Alcohol
– Infectious diseases
– Occupational exposures
– Environmental exposures
– Drugs abused
– Medication
– etc.
Placenta

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 NOT barrier protecting the fetus from drugs
administered to its mother
Fetal rubeolla syndrome
Fetal aminopterine syndrome
Fetal hydantoine syndrome
Fetal valproate syndrome
Fetal warfarin syndrome
Fetal alcoholic syndrome
Fetal hyperpyretic syndrome
Medications

Over-the-counter medicines



Herbals and dietary supplements
Prescription drugs
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
Undetermined
None, Minimal or Unlikely
Small, Moderate or High
100%
80%
60%
40%
20%
0%
0-4
5-9
10-14
15-20
Years Since FDA Approval
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
Animal teratology studies
are valuable
but …
false positives and
false negatives do
occur.
Animal Teratology Studies: False
Positives

corticosteroids

chlorpheniramine

hydroxyzine

propoxyphene
Animal Teratology Studies: False
Negatives

ACE inhibitors: captopril, enalapril 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.

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.
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
substances in pregnant
women is
unallowable
Mechanisms of impairments


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 identification of
teratogenity in human pharmacology

Case-reports – lithium – hearth malformations

Case-control studies – stilbestrol – vaginal adenoca,
ASA in I. trimester (teratogenic in animals)

Cohort studies (prospective) – fluoxetine

(Interventional studies) – RCT – folic acid (0.8 mg daily
in prevention of neural schisis)

Meta-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
Conclusions

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 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 pregnancy
regarding the effects of 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 2a etc.)
Rey, 2007
Antiastmatics during pregnancy I.

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 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 pregnancy II.

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 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