This document discusses drug use during pregnancy and factors that can influence drug effects. It notes that physiological changes during pregnancy can alter how drugs are absorbed, distributed, metabolized and excreted in the mother's body. The critical period of fetal development, when the embryo is most vulnerable to drug-induced teratogenesis, is between 20-60 days or 5-10 weeks of gestation. Drug selection during pregnancy involves weighing risks to the fetus from maternal illness versus risks of drug exposure. For less serious conditions, safer drugs should be chosen, but in life-threatening situations the risks of untreated illness may outweigh potential teratogenic effects.

1. Drug Use Around Pregnancy &Drug Use Around Pregnancy &
TeratogenicityTeratogenicity
Dr. Mamdouh SabryDr. Mamdouh Sabry
MD. Ain Shams, Ph.D. FranceMD. Ain Shams, Ph.D. France
Consultant Ob. & GynConsultant Ob. & Gyn..
EL Mataria Teaching Hospital, Nasser InstituteEL Mataria Teaching Hospital, Nasser Institute
Cairo, EgyptCairo, Egypt

2.  Most women are exposed to specific and nonMost women are exposed to specific and non
specific drugs during their reproductive lifespecific drugs during their reproductive life
which might affect their pregnancy outcome.which might affect their pregnancy outcome.
 The general principles of drug therapy isThe general principles of drug therapy is
applied to pregnant women as much as anyapplied to pregnant women as much as any
other patient.other patient.
 The physiologic changes which may alter drugsThe physiologic changes which may alter drugs
effect during pregnancy and the effect of drugseffect during pregnancy and the effect of drugs
on the embryo and mother are considered andon the embryo and mother are considered and
has to be evaluated.has to be evaluated.

3. HOST FACTORSHOST FACTORS
(Maternal pharmacokinetics)(Maternal pharmacokinetics)
1)1) Decrease overall serum concentrationDecrease overall serum concentration
of most drugs.of most drugs.
2)2) Decrease drug absorptionDecrease drug absorption
3)3) Increase excretion and clearance ofIncrease excretion and clearance of
most of the drugs.most of the drugs.
4)4) Increase incidence of infection.Increase incidence of infection.

4. HOST FACTORSHOST FACTORS
(Maternal pharmacokinetics)(Maternal pharmacokinetics)
1)1) Decrease overall serum concentration of drugs:.Decrease overall serum concentration of drugs:.
 GIT changes.GIT changes.
 ↓↓ serum albumin 20%.serum albumin 20%.
 Blood volume ↑→ ≤Blood volume ↑→ ≤ 45% (1500ml).45% (1500ml).
 Plasma volume ↑→ ≤ 50% (1300ml).Plasma volume ↑→ ≤ 50% (1300ml).
 ↑↑ Total body water → ≤ (2000ml).Total body water → ≤ (2000ml).

5. HOST FACTORSHOST FACTORS
(Maternal pharmacokinetics)(Maternal pharmacokinetics)
2)2) Increase excretion and clearance of many drugs:.Increase excretion and clearance of many drugs:.
 ↑↑ Renal blood flow ≤ 30%Renal blood flow ≤ 30%
 ↑↑ GFR ≤ 50%GFR ≤ 50%
 ↑↑ Creatinine clearance.Creatinine clearance.

6. HOST FACTORSHOST FACTORS
(Maternal pharmacokinetics)(Maternal pharmacokinetics)
3)3) ↑↑Incidence of infection:.Incidence of infection:.
 UTI.UTI.
 Vaginitis → PROM.Vaginitis → PROM.
 Gall bladder → stasis, emptying.Gall bladder → stasis, emptying.

7. Drug effects on FetusDrug effects on Fetus
 Congenital malformations among liveCongenital malformations among live
births represent about 3-5%.births represent about 3-5%.
 65% → unknown causes.65% → unknown causes.
 Drug induced → ≤ 1%Drug induced → ≤ 1% (Schardein. JL 2000),(Schardein. JL 2000),
no data to confirm the 1-3% issue.no data to confirm the 1-3% issue.

8. Paternal & maternal drug exposure
-Paternal and maternal drug exposure before
conception is addressed recently.
-Chemotherapy, radiotherapy, interferon,
environmental toxins, monoclonal antibody
and others, alter production, shape, size and
performance of sperms ( chromosomal
abnormality . Ova & embryo???
-Animal studies has shown that paternal
teratogenic exposure may lead to pregnancy
loss or failure of the embryo to develop.

9. -At present, no evidence shows that paternal
exposure directly increases risk of birth
defects.
-Chemotherapy or radiotherapy may increase
risk of chromosomal abnormality or affect
fertility, semen and ova banking and, or
pregnancy delay for 3 months are solutions.
-Additional research must be conducted to
evaluate fertility and pregnancy outcome in
cancer patients, as there number is
increasing during age of reproduction.

10. FDA pregnancy risk categories:.FDA pregnancy risk categories:.
A.A. Controlled studies show no risk.Controlled studies show no risk.
B.B. +ve risk in animals & -ve risk in humans on+ve risk in animals & -ve risk in humans on
controlled studies, or –ve risk in animals ?!controlled studies, or –ve risk in animals ?!
C.C. Risk can not be ruled out; lacking wellRisk can not be ruled out; lacking well
controlled human studies or animal studies ascontrolled human studies or animal studies as
well, or even may show risk → benefits x riskwell, or even may show risk → benefits x risk
most drugs are category C;most drugs are category C; (aminoglycosides)(aminoglycosides)
D.D. +ve evidence of risk in humans but risk is+ve evidence of risk in humans but risk is
acceptable x potential benefits;acceptable x potential benefits; (epilepsy)(epilepsy)
X.X. Contraindicated; risk outweighs benefit.Contraindicated; risk outweighs benefit.

11. pregnancy risk categoriespregnancy risk categories
Pregnancy CategoryPregnancy Category
AnimalAnimal
ExposureExposure
HumanHuman
ExposureExposure
AA -- --
BB ++
--
--
??
CC ++
??
??
??
DD (benefit may outweigh risk)(benefit may outweigh risk) ++ ++
XX (contraindicated)(contraindicated) ++ ++
- No risk; + known risk; ? No information available.- No risk; + known risk; ? No information available.

12. Exposure Time & RiskExposure Time & Risk
 Conception →Conception → 2020 days (days (55thth
. Week) (complete. Week) (complete
repair x fetal wastage).repair x fetal wastage).
 Critical periodCritical period → organogenesis→ organogenesis 20-6020-60 days,days,
((5-105-10 weeks) during which embryo is mostweeks) during which embryo is most
vulnerable to insult. (Refampin → renal tubularvulnerable to insult. (Refampin → renal tubular
defects, facial clefts).defects, facial clefts).
 Second trimester → avoid agents withSecond trimester → avoid agents with
antimetabolic action (trimethoprim; anti-folate).antimetabolic action (trimethoprim; anti-folate).
 Third trimester → (near term), affect newbornThird trimester → (near term), affect newborn
babies (chloramephinicol, sulfonamides).babies (chloramephinicol, sulfonamides).

13. Example teratogenesis mechanisms
-Excessive apoptosis noticed with teratogens
like cyclophosphamide, tumor necrosis
factor-alpha, transforming growth factor-
beta and other cytokines.
-Granulocyte-macrophage colony-stimulating
factor prevents teratogenesis in lab animals.
-Immunomodulation and hormonal support
( like progesterone or HCG supplements)
can module the balance between the
manifold cytokines, non of them proven
beneficial.

14. Examples
-Transplantation, liver, kidney, heart & lung;
steroids, azathioprine, mycophenolate
-Antibiotics…peni, ceph, macrolides, B lact..
-Chemotherapy; glevic, HMU, MCA, Inerfer..
-Thyroid; PTU(150-400), methimazol(15-40).
-Epilepsy…phenobarb., carbamaz., epan.
-Imaging; Xray(0.05-0.5), CT(0.05-0.07),MRI
-Hematology; Thrombocytosis , Thromb..a,
thalas. …. .

15. Antibiotics in pregnancy
-Safe antibiotics: penicillins, cephalosporins,
macrolides, lincosamide, vancomycin, , aztronam,
imepenem and meropenm, ethambutol, INH +
pyridoxene , metronidazol, chloroquine and
mebendazol.
-Antibiotics with caution: aminoglycides, linizolid,
rifampin, droipenem, etrapenem, nitrofurantoin and
azoles.
-Contraindicated: Chloramphenicol, quinolones,
tetracyclines (more than 15 wks, tigecycline),
sulfonamides and streptomycin.
- Serum level is kept in mind, MIC.

16. Antiepleptics
-Older group: Carbamazepine, phenytoin,
valproic acid, phenobarbital and primidone...
-Second generation: Of high interest with
lamotrigine as safest, while promising data
appear for leviteractam and oxcarbazepine,
topiramate, zonisamide, gabapentin and
pregabolin are in progress.
-Monotherapy, folic acid, contraception & lact. .
-Used for ttt of bipolar disorders, neuropathic
pain, anxiety disorders and migraine.

17. Antacids & GERD
• Al. and mg. salts as well as sucralfate decrease
GERD, safe but decrease iron and calcium abs..
• H2 receptor antagonists are most commonly used
safest drugs during pregnancy, category B,
cimetidine, rantidine as well as famotidine which is
considered the maximum acid reducer with
decreased noctornal hyperacidaemia and least
concentration in milk.
• Proton pump inhibitors may be given, omperazole
is first investigated, pantoprazol, lansoprazol and
esmoprazole follow.

18. ConclusionConclusion
 Drug use around pregnancy requires analysisDrug use around pregnancy requires analysis
and consideration of hazards of gonadotoxicand consideration of hazards of gonadotoxic
drugs, of maternal physiology and fetal riskdrugs, of maternal physiology and fetal risk
during all trimesters.during all trimesters.
 For less serious diseases, the safest drugFor less serious diseases, the safest drug
should be selected.should be selected.
 In life-threatening diseases, the risk ofIn life-threatening diseases, the risk of
morbidity or mortality may overshadow themorbidity or mortality may overshadow the
possibility of teratogenic side effects.possibility of teratogenic side effects.
 However, once condition is stable the safestHowever, once condition is stable the safest
drug should be used.drug should be used.