FACULTY OF OBSTETRICS AND

GYNAECOLOGY
NATIONAL POSTGRADUATE
MEDICAL COLLEGE OF NIGERIA

PRIMARY REVISION COURSE IN BASIC

MEDICAL SCIENCES
TRAUMA CENTRE
NATIONAL HOSPITAL, ABUJA
19TH- 24TH FEBRUARY 2018
DRUG AND THE FETUS

DR. KOREDE DUROJAIYE MBBCH,FWACS,FMCOG

SENIOR CONSULTANT OBSTETRICIAN AND
GYNAECOLOGIST
NATIONAL HOSPITAL, ABUJA
OUTLINE
OBJECTIVE
INTRODUCTION
HISTORICAL PERSPECTIVES
EFFECT OF PREGNANCY ON DRUGS
DRUGS AND TERATOGENESIS
MECHANIS NOF ACTIONS
SOME DRUGS AND ITS EFFECT
DRUGS AND LACTATION
CONCLUSION
OBJECTIVE
Understand what drug and the fetus
implies
Discuss guidelines for prescribing drugs
in pregnancy
Discuss teratogenicity and the
mechanism of action of teratogenic
drugs
Common drugs use in pregnancy and
their possible teratogenic effect
Highlight safe drugs in pregnancy
Discuss substance abuse in pregnancy
Drugs and lactation
INTRODUCTION
If you are pregnant or thinking about
getting pregnant and want a healthy
baby, then it is very important to avoid
drug use during pregnancy.
Illegal, Illicit, over the counter drugs
and substances abuse such as
caffeine and alcohol can have long
lasting effect on the unborn child
DEFINITION
Drug is defined as an article other than food that
is intended for use or used in the diagnosis, cure,
mitigation, treatment or prevention of disease, or is
intended to affect the structure or any function of
the body. The term does not include a device, or a
component, part or accessory of a device.

It includes a chemical substance that affects the

processes of the mind or body or a substance
used recreationally for its effects on the central
nervous system, such as a narcotics
A fetus is a prenatal human between
the embryonic state and birth. The
fetal stage of human development
tends to be taken at beginning of nine
weeks.
However in biological terms, however,
prenatal development is a continuum,
with no clear defining feature
distinguishing an embryo from a
fetus.
HISTORICAL PERSPECTIVE
Thalidomide was used in the late 1950s and
early 1960s to combat morning sickness, but
led to children being born without limbs.
Diethylstilbestrol (DES) use b/w 1940 and
1971 to prevent miscarriage, premature
labour, and related complications of
pregnancy was found to be related to clear
cell adenocarcinoma of the cervix and
vagina.
Isotretinoin used for acne causes birth defect
and spontaneous abortion.
Benedectin (1982)
WHY DRUG DURING PREGNANCY
Total avoidance of pharmacological treatment in pregnancy is
not possible and may be dangerous
Medical conditions prior to pregnancy may require ongoing and
episodic treatment (e.g. HIV, asthma, epilepsy, diabetics,
hypertension).
During pregnancy new medical problems may develop
Old medical condition can be exacerbated (e.g. migraine,
headache) requiring pharmacological therapy.
The fetus can developed problem that necessitate the use of
drug
Uterine contraction
Steroids for lung maturation
Magnesium sulphate for Preeclampsia and for neuroprotection
During labour, dugs might be needed
Post labour management.
EFFECT OF DRUGS ON THE FETUS
They can act directly on the fetus, causing
damage, abnormal development (leading to
birth defects), or death.
They can alter the function of the placenta,
usually by causing blood vessels to narrow
(constrict) and thus reducing the supply of
oxygen and nutrients to the fetus from the
mother.
Sometimes the result is a baby that is
underweight and underdeveloped.
They can cause the muscles of the uterus
to contract forcefully, indirectly injuring the
fetus by reducing its blood supply or
triggering preterm labour and delivery.
It may cause uterine relaxation leading to
prolonged pregnancy
They can also affect the fetus indirectly. For
example, drugs that lower the mother's
blood pressure may reduce blood flow to
the placenta and thus reduce the supply of
oxygen and nutrients to the fetus.
EFFECT OF DRUGS ON THE FETUS

It may affect the liquor volume

It could affect the baby central
nervous system causing long term
sequeale
It could result in neonatal jaundice
May pass through breast milk and this
may affect the baby
DETERMINANT OF THE EFFECT
OF DRUGS IN PREGNANCY

The effects depends on

Stage of Development of the fetus
(Gestational Age)
Strength of the Drug
Dosage of the Drugs
Chemical Structures of the Drugs
EFFECT OF PREGNANCY ON DRUGS

Drug Choice
Drug Ingestion
Drug Distribution
Absorption
Metabolism
Excretion
DRUG USE IN THE FIRST TRIMESTER
This is characterized by the embryonic
period ( conception to 8weeks) and early fetal
period.
Drugs at this stage may cause teratogenicity.
Teratogenicity is defined as the origin or
mode of production of congenital anomalies;
the disturbed growth processes involved in
the production of a malformed neonate.
Drug use after the 8weeks may cause subtle
defect, but tend to have profound effect on
the brain and general growth of the fetus.
TIME AND EFFECT
Possible Drug Status of the
Time Frame
Effects Fetus
An all-or-nothing
The fetus is highly
effect (death of the
Within 20 days resistant to birth
fetus or no effect
after fertilization defects.
at all)

Possibly no effect
The fetuses
A miscarriage
organs are
An obvious birth
3‒8 weeks after developing,
defect
fertilization (Period making the fetus
A permanent but
of organogenesis) particularly
subtle defect that
vulnerable to birth
is noticed only
defects.
later in life
TIME AND EFFECT
After organogenesis, in the 2nd and
3rd trimester, teratogenesis is
unlikely, but drugs may alter growth
and function of normally formed fetal
organs and tissues.
However, as placental metabolism
increases, doses must be higher for
fetal toxicity to occur.
DRUGS AND
TERATOGENESIS
Teratogenesis is the disturbed growth
processes involved in the production of a
malformed neonate.
It results from the effects of teratogens
Teratogens inludes
• Chemical (Drugs)
• Biological (Infections)
• Physical (Radiation)
DRUGS AND
TERATOGENESIS

Drugs account for 2-3% of birth

defects (3-5% of live births are born
with birth defects each year).
These drugs are prescription drugs
taken to treat a disorder or symptoms
TERATOGENIC
MECHANISMS OF DRUG
USE IN PREGNANCY
Six teratogenic mechanisms associated
with medication use:
• folate antagonism,
• neural crest cell disruption,
• endocrine disruption,
• oxidative stress,
• vascular disruption and
• specific receptor- or enzyme-mediated
teratogenesis.
FOLIC ACID ANTAGONISM
Several drugs disturb the folate metabolism
through inhibition of the folate methylation cycle.
Two general groups of drugs act as folate
antagonists.
The first group are competitive inhibitors of DHFR
and includes Methotrexate, Sulfasalazine,
Triamterene and Trimethoprim, which block the
conversion of folate to DHF by binding irreversibly
to the enzyme
The second group impair folate absorption or
increase folate degradation. Mainly antiepileptic
Valproic acid, Carbamazepine and Phenytoin.
NEURAL CELL CREST DISTRUPTION
Neural crest is a pluripotent cell population that
originates in the neural folds and migrate into the
embryo to give rise to numerous structures.
Proper induction, migration, proliferation and
differentiation of neural crest cells are tightly
regulated.
Fibroblast growth factors, Integrins , Pax3,
Endothelins and their receptors may be required.
Therefore, drugs that interfere with these
molecular pathways, such as Bosentan and
excess Vitamin A , Retinoids will all cause
malformations
ENDOCRINE DISTRUPTION
Some hormonal drugs including diethylstilbestrol
(DES), oral contraceptives and hormones used in
fertility treatment and other endocrine disrupting
chemicals (EDCs), such as bisphenol A and
phthalates, may interfere with the physiologic
functions of endogenous hormones by affecting their
release, binding or metabolism.
Their actions may not only depend upon their affinity
or specificity for the estrogen and/or androgen
receptors, but also upon their ability to activate or
inhibit receptor-mediated actions, which are
dependent upon the absorption, distribution,
metabolism and excretion of these molecules as well.
OXIDATIVE STRESS
Oxidative stress, an imbalance between reactive
oxygen species generation and antioxidant
defense mechanisms of a cell or tissue, causes
irreversible oxidation of DNA, proteins and lipids,
leading to inactivation of many enzymes and cell
death.
It may affect gene expression by interfering with
the activity of redox-sensitive transcription factors
and signal transduction by oxidizing thiols.
Drugs known to induce oxidative stress includes
thalidomide (Hansen and Harris, 2004), phenytoin,
valproic acid, class III antiarrhythmic drugs, iron
supplements and various chemotherapeutic drugs.
 VASCULAR DISTRUPTION
Vascular disruption refers to disturbances in the blood
circulation in the uterine-placental unit, the placental-
fetal unit or the fetus itself. These disturbances include
hyperperfusion, hypoperfusion, hypoxia and obstruction.
Vasoactive therapeutic drugs that have reported
associations with the vascular disruption defects
described below include misoprostol, aspirin ,
ergotamine and pseudoephedrine. However, all drugs
with vasoconstrictive or vasodilating effects may have
the potential to cause birth defects due to vascular
disruption.
SPECIFIC RECEPTORS OR ENZYME
MEDIATED TERATOGENESIS
Angiotensin-converting enzyme and angiotensin II receptors
–renal tubular dysgenesis and oligohydramnious
Hydroxymethylglutaryl-coenzyme A reductase affect normal
growth pattern
Histone deacetylase- neural tube defect.
Cyclooxygenase-1 results in increased risk of orofacial clefts
and cardiovascular defects, especially cardiac septal defects
N-methyl-d-aspartate receptors affect neuronal development
5-Hydroxytryptamine receptors and transporters – neural
tube defect
γ-Aminobutyric acid receptors – benzodiazepine (flooping
infant syndrome)
Carbonic anhydrase – limbs deformities
EFFECT OF TERATOGEN ON
THE FETUS
Cell Death
Reduced cell division
Disruption of cell migration
Disruption of induction, proliferation and
differentiation of cells
Mechanical disruption
Failure of normal interaction between cells
DRUG USE IN THE SECOND AND THIRD
TRIMESTER
Most drug not safe in the first trimester are safe at
this period. Including drugs that are necessary in
pregnancy. E,g Fansidar, It is safe in second
trimester and early third trimester
This is due mainly to the effect of placenta.
Placental structure, cellular composition, function
and blood flow change with gestational age, which
alters placental uptake and transport.
Therefore for a drug to have effect on the fetus at
this age it must have high permeability via
placenta or must be able to stay in the system for a
long period and get transfer during the delivery or
when there is shearing of the placenta.
Other reasons is the fact that
organogenesis have been completed,
however it has been found that most
of the organs are still growing, hence
any drugs that can cross the placenta
barrier may affect the fetus.
Other indirect effects of drugs
On the uterine muscle
Affect placenta blood flows
GUIDES TO DRUG USE IN PREGNANCY
Avoid drugs in the first trimester
Use only well known and older drugs
with known safety index.
Substitute potential harmful drugs with
safe and well known drugs.
Highly toxic drugs should never be used
during pregnancy.
For patient on toxics drugs, give some
time after stoppage before advising
conception
The drug doses at the lower end of the
therapeutic range should be prescribed
during pregnancy
Avoid the used of over the counter drugs
Drugs should not be taken without
prescription from a physician.
Where a physician is not sure of the safety
of a drug in pregnancy, he should avoid it
or asked for a second opinion
FDA CATEGORIES OF DRUG
SAFETY DURING PREGNANCY
Category A- Well controlled studies in
women fail to demonstrate a risk to the
foetus. These drugs are the safest
E.g. levothyroxine, folic acid, liothyronine
Category B- Animal studies do not show a
risk to the foetus, but there are no
controlled human studies or animal studies
show a risk to the fetus, but well controlled
human studies do not.
E.g: metformin, hydrochlorothiazide,
cyclobenzaprine, amoxicillin, pantoprazole
FDA CATEGORIES…..
Category C- No adequate studies in
animal or human or animal studies
shown teratogenicity or embryocidal
effect, no controlled studies in women.
E.g: tramadol, gabapentin, amlodipine,
trazodone

Category D- Positive evidence of human

foetal risk exits but benefit may
outweigh risk in certain situations like
life threatening conditions in which
safer drugs is ineffective. E.g: lisinopril,
alprazolam, losartan, clonazepam,
lorazepam
FDA CATEGORIES…..
Category X -Studies in animals or
human have demonstrated foetal
abnormalities or there is evidence
of foetal risk based on human
experience, or both, and risk clearly
outweighs any possible benefit.
E.g: atorvastatin, simvastatin,
warfarin, methotrexate, finasteride
SOME DRUGS AND THEIR EFFECT
ANTIBIOTICS
Aminoglycosides & Streptomycin: Ototoxicity
Chloramphenicol: Gray baby syndrome, Haemolysis
Nitrofurantoin and Primaquine: Haemolysis
Fluoroquinolones: Musculoskeletal defects
Trimethoprim: Increased neural tube defect
Tetracycline: Enamel hypoplasia/yellowishness
ANTICOAGULANT
Warfarin: Ist trimester(nasal hypoplasia, bilateral
optical atrophy, intellectual disability)
2nd or 3rd trimester(optic atrophy, cataract etc)
SOME DRUGS AND THEIR EFFECT
LMW and Unfractionated Heparin:
Thrombocytopaenia and maternal bleeding
ANTICOVULSANT
Carbamazepine: NTD and Haemolysis
Phenobarbital: Haemolysis, Some malf.
Valproate: NTD incl. meningomyelocele
Phenotyoin: cleft lip, genitourinary defect
ANTIHISTAMINE
Meclizine: teratogenic in rodent. No proof in
human
SOME DRUGS……………….
ANTIHYPERTENSIVE
Beta blocker: Fetalbradycardia, hypoglycaemia
ACE Inhibitors: Renal defect, limb defect,
oligohydramnios, craniofacial def.
Ca channel blockers: Phalanges deffect (1st
trimester), IUGR (2nd and 3rd trimester)
Thiazide diuretics: IUGR, Neonatal
hyponatremia, hypokalemia
ORAL HYOPGLYCAEMIC DRUGS
All causes neonatal hypoglycaemia
SOME DRUGS………………………
ANTIMALARIA
Halofantrine: ? Teratogenic effect.Not
recommended in pregnancy
Doxycyline: Enamel hypoplasia/Discoloration
Sulphadoxine: Neonatal hyperbilirubinemia
Hydroxychloroquine: no risk at normal dose.
THYROID DRUGS
Methimazole,Propylthiouracil, Radioactive
iodine,triiodothronine: Fetalgoiter
VITAMIN A (ISORETINOL): Structural abnorm.
Mental retardation
VITAMIN K: Haemolysis in G6PD
SOME DRUGS…………………..
ANTINEOPLASTIC DRUGS
Actinomycin: Teratogenic proof only in animal
Busulfan, Chlorambucil, Cyclophosphomide,
Methotrexate, Mercaptopurine: Cleft palate, IUGR,
ear defect, club foot, spinal defect, cranial
dysostosis, mandibular defect.
Colchicine: Congenital mal, Sperm abnormalities.
Vincristine , Vinblastine: Teratogenic in animal, no
human studies.
ANXIOLYTICS:
Benzodiazepines: ( Late in preg.)Resp. depression,
infant withdrawal syndrome
VACCINES IN PREGNANCY
All live virus , live virus attenuated and live
bacteria vaccines have potential risk to the
fetus and thus contraindicated in pregnancy.
If needed, they should be given at least a
month or more before pregnancy
Contraindicated vaccines
Measles, Mumps, Rubella, Polio, HPV,Influenza
(live activated), Varicella, Zoster, Anthrax,BCG,
Smallpox , Yellow fever. Typhoid,
Meningococcal, Pnuemoccocal, Japanese
encephalitis.
Non contraindicated vaccines in
pregnancy
Hepatitis B
Influenza (inactivated)
Tdap ( Tetanus, Dipteria and
Pertusis)

.
 VACCINE DURING BREASTFEEDING
Inactivated, recombinant, subunit,
polysaccharide, and conjugate vaccines, as
well as toxoids, pose no risk for mothers who
are breastfeeding or for their infants.”
Although neither inactivated nor live-virus
vaccines administered to a lactating woman
affect the safety of breastfeeding for women or
their infants
It is recommended that all live , live attenuated
and live bacteria vaccine should be avoided in
lactating mother or if requires, the mother
should stop breastfeeding
ANAESTHETICS AGENT
LOCAL ANAESTHETICS AND OPIODS
ANALGESIC usually cross the placenta and
can affect the newborn.
It does not appear that anaesthetic agents
have teratogenic effects in humans.
However anaesthesia and surgery during
pregnancy are associated with an increased
risk of miscarriage, premature birth, low birth
weight infants and infant death.
SOCIAL DRUGS
AMPHETAMINES: Heart defect, IUGR
CAFFEINE: consumption of over 300mg per day causes
an increase in term low-birth-weight infants,< 2500g at
greater than 36 weeks.
COCAINE: associated with higher rate of spontaneous
abortion, abruptio placenta, low birth weight,
microcephaly.
MARIJUANA: increased risk of precipitate labour(<3hrs)
and low birth weight
NARCOTICS: increased risk of abortion, prematurity,
and growth restriction, neonatal withdrawal syndrome
TOBBACO: associated with a fourfold increase in small
size for gestational age as well as an increased
prematurity rate.
ALCOHOL: Causes fetal alcohol syndrome
SOME COMMON SAFE DRUGS IN
PREGNANCY
ANTACIDS / REFLUX / UPSET STOMACH
Gaviscon/ Gestid/ Mist. Magnesium trisilicate
Pepcid (famotidine)
Zantac (ranitidine)
Tagamet (cimetidine)
Aciphex (rabeprazole) Rx
Nexium (lansoprazole) Rx
Prevacid (pantoprazole) Rx
Prilosec (omeprazole)
Protonix Rx (pantoprazole) Rx
ANTIBIOTICS
Amoxicillin, ampicillin Rx
Augmentin (amoxicillin +clavulanate) Rx
Clindamycin Rx
Erythromycin Rx
Keflex (cephalexin) Rx
Macrobid, Macrodantin (nitrofurantoin) Rx
Metronidazole Rx
Zithromax (azithromycin) Rx
ANTIMALARIA
Chloroquine
Amodiaquine
Quinine
Azithromycin
Clindamycin
Sulfadoxine-pyrimethamine
Mefloquine
Dapsone-chlorproguanil
Artemisinin derivatives
Atovaquone-proguanil
Lumefantrine.
ANTIEMETICS
Doxylamine (Unisome sleep tabs)
Kytril (granisetron) Rx
Phenergan (promethazine)Rx
Reglan (Metoclopramide) Rx
Zofran (ondansetron)Rx

ANTIDIARRHEALS
Imodium capsules (loperamide)
ANTIFUNGALS
Diflucan (fluconazole) Safe in all trimester
Gynazole 1 (butoconazole) Safe only in 2nd and 3rd
trimester
Gynelotrimin 3 or 7day (clotrimazole) Use after 1st trim.
Monistat 1day (miconzole,ticonazole) Use after 1st trim.
Monistat 3 or 7day (miconazole) Use after 1st trim.

TOPICAL CREAMS / OINTMENTS

Benadryl, hydrocortisone, caladryl
ANTIVIRALS
Famvir (famcyclovir)
Valtrex (valcyclovir)
Tamiflu
Zovirax (acyclovir)
PAIN / FEVER
Naproxen sodium Only in 2nd trimester
Low dose Aspirin
Ibuprofen Only in 2nd trimester
Acetaminophen
Tylenol with codeine Rx
LAXATIVES / STOOL SOFTENERS
Citrucel (methylcellulose powder)
Colace (docusate sodium)
Dulcolax Tablets (Bisacodyl)
Lactulose
Milk of Magnesia
Miralax (PEG)
Senokat (senna tablet)
ANTIHISTAMINES/DECONGESTANTS/COUGH/COLD
Allegra (fexofenadine) Rx
Benadryl (diphenhydramine)
Chlor trimeton (Chlorpheniramine)
Clarinex, Alavert (loratadine)
Cough Drops
Mucinex ( guaifenesin)
Mucinex D (guaifenesin+pseudoephedrine) Use
after 1st tri.
Rhinocort Aqua
Robitussin Cough, Delsym (dextromethorphan)
Robitussin DM (dextromethorphan + guaifenesin)
Sudafed (pseudoephedrine) Use after 1st trimester
 DRUGS AND BREASTFEEDING
Some drugs crosses to the baby via breastmilk
Some of these drugs can still have harmful effect
on the baby and should be avoided.
These drugs includes
Benzodiazepam
Lithium
Carbimazole
Barbiturates
Indomethacin
Laxatives
Some vaccines
CONCLUSION
Every drug is potentially harmful to the
fetus
Only well known drugs with good safety
index should be prescribed in pregnancy
Proper education of pregnant women
and those intending to get pregnancy
about drug use as well as use of social
drug should be carried out at all
antenatal and gynaecological clinics.
THANKS…………………
AND WISHING YOU
BEST OF LUCK IN
YOUR EXAMINATION