Drugs used in pregna

ncy

Dr. Vikas S. Sharma

MD Pharmacology
 Overview
 Introduction

 Pharmacokinetics & pharmacodynamics in pregnancy

 Teratology

 Various drugs used in pregnancy

 Known teratogenic drugs

 Summary
 Drug Epidemiology
 More than 90% of pregnant women take prescribed or
non-prescribed (OTC) medicines or use social drugs (like
tobacco and alcohol) or illicit drugs at some time during
pregnancy

 In general, drugs should NOT be used during pregnancy

unless absolutely necessary as many can harm fetus

About 2-3% of all birth defects result from drugs that are
taken to treat disorder or symptom
Pregnancy induced maternal physiologi
c changes

 Gastrointestinal absorption
 ↓ GI motility - Secondary to progesterone levels
 ↓ gastric acid secretion
 ↑ gastric mucus secretion
 ↑ Gastric emptying time
Pregnancy induced maternal physiologic changes…

 Lung absorption
 Cardiac and tidal volumes ↑ by ~ 50%
 Hyperventilation and ↑ pulmonary blood flow

 Transdermal absorption
 ↑ in peripheral vasodilation &
↑ in blood flow to skin
 ↑ transdermal absorption
Pregnancy induced maternal physiologic changes…

Organ System Dynamic Change during pregnancy

Cardiovascular
Blood volume Increased by 30-50%
Cardiac output Increased by 30-50%
Systemic vascular resistance Decreased

Organ System Dynamic Change during Pregnancy

Gynecologic
Uterine Blood Flow Increased
 Metabolism
 Hepatic drug metabolising enzymes - induced
during pregnancy, probably by high levels of
circulating progesterone

 This leads to rapid metabolic degradation,

especially of lipid soluble drugs
 Excretion
Organ System Dynamic Change During Pregnancy
Kidney
Renal Blood Flow rate Increased
Glomerular Filtration rate Increased
 Placental Pharmacokinetics
1. Physicochemical properties of drug

a) Lipid solubility - lipophilic drugs tend to diffuse

readily across placenta easily, whereas highly ionized
drugs cross placenta slowly & achieve very low conc.
in foetus
If high enough maternal-foetal conc. gradients are
achieved, polar compounds cross placenta in
measureable amounts

b) Molecular size - drugs with low mol. wt. ( 500 D)

cross placenta easily
Placental Pharmacokinetics...

2. Rate at which drug crosses placenta & amount of

drug reaching foetus

a) Placental transporters - these transporters pump

drug from foetal blood back in to maternal blood,
e.g.: P-gp, BCRP, MRP3

b) Protein binding - affect rate & amount of transfer

c) Placental metabolism - may convert toxic drugs to

nontoxic metabolites
Placental Pharmacokinetics...

 Blood flow through placenta ↑ during gestation

 Compounds that alter blood flow alter maternal drug

disposition & placental transfer

 Placental metabolism (dealkylation, hydroxylation,

demethylation) affects drug transfer across placenta

 At term, surface area of placenta is at its maximum &

nearly all substances can reach fetus
 Fetal Pharmacokinetics
 Plasma binding proteins differ from maternal

 Drugs transferred across placenta undergo

1st pass metabolism through fetal liver

 Liver expresses metabolizing enzymes, capacity is

not fully developed

 Fetal kidney is immature

 Pharmacodynamics in pregnancy
 Maternal drug actions - effects of drugs on
reproductive tissues (breast, uterus, etc.) may sometimes
be altered; however, effects on other maternal tissues
are not changed significantly by pregnancy

 Therapeutic drug actions in foetus - foetus may be

drug target
E.g. Steroids used to stimulate foetal lung maturation
when preterm birth is expected
Pharmacodynamics in pregnancy...

 Predictable toxic drug actions in foetus - use of ACEIs

during pregnancy can cause irreversible renal damage
in foetus due to foetal hypotension

 Teratogenic drug actions - drugs may interfere with

passage of O2 or nutrients through placenta & thus
have effects on most rapidly metabolising tissues
E.g. thalidomide, Vitamin A analogues or folate
deficiency
 The issues
 Only half of all pregnancies are planned
 Many women need medications for pregnancy induced
conditions e.g.
 Morning Sickness,
 Chronic conditions (e.g. epilepsy)
 Intercurrent conditions (allergies)
 Diabetes
 Hypertension
 Women work with chemicals, exposed to radiation &
use illicit drugs
Pregnancy Risk Categories - FDA
 Category A: Safety has been established using human
studies, no fetal risk (Thyroxine,
magnesium sulfate)
 Category B: Presumed safety based on animal studies,
but no well-controlled human studies
(Penicillin, amoxicillin, erythromycin)
 Category C: Uncertain safety. Animal studies show
adverse effect, no human studies
(Morphine, codeine, atropine)
Pregnancy Risk Categories – FDA...

 Category D: Evidence of fetal risk, but benefits

outweigh risks (Aspirin, phenytoin, methotrexate)

 Category X: Highly unsafe. Risk outweighs any benefit

(Estrogen, thalidomide, isotretinoin)
Pregnancy & Lactation Labelling Rule (P
LLR)
8.1 - Risk Summary, Clinical
considerations and Data,
pregnancy exposure registry
8.2 - Breastfeeding, drugs in breast
milk and effects on infant
8.3 - pregnancy testing,
contraception recommendations
& infertility information

 Final Rule 12.4.2014 – To improve content and format of treatment labeling

 Replaces pregnancy letter categories – A, B, C, D and X established in 1979
Too simplistic, misinterpreted, misinformed regarding treatment choices
 Replaces letters with narratives addressing potential risks & benefits of
treatment during pregnancy & lactation
 Teratology
 Branch of medical sciences devoted to the study of the
environmental contribution of abnormal prenatal
growth & development

 Term is derived from Greek “teratos = monster”

 Teratogen – An agent or factor which can cause

abnormalities of form & functions (birth defects) in an
exposed embryo or fetus
 TERATOGEN
In 1959, James Wilson - 6 basic principle of teratology

1. Susceptibility to teratogenesis depends on genotype of

conceptus & manner in which it interacts with
environmental factors

2. Susceptibility to teratogens varies with developmental

stage at time of exposure

3. Teratogenic agents act in specific ways on developing

cells & tissues to initiate abnormal developmental
processes
TERATOGEN...

4. Access of adverse environmental influences to

developing tissues depends on nature of influences

5. Final manifestations of altered development are

death, malformation, growth retardation and
functional disorder

6. Manifestations of altered development increase in

frequency & in degree as dosage increases from no
effect to 100 % lethality
TERATOGEN...
To be considered teratogenic, a candidate substance or
process should
i) result in characteristic set of malformations
ii) exert its effects at particular stage of foetal
development
iii) show dose dependent incidence

 Baseline teratogenic risk in pregnancy is about 3 %

 Teratogenesis
 Defined as structural or functional dysgenesis of fetal
organs
 Typical manifestations include
 Congenital malformations with varying severity
 Intrauterine growth restriction
 Carcinogenesis
 Fetal demise
Drug Disposition In Maternal-fetal Un
it
EFFECT OF DRUGS ON PREGNA
NCY
1. Pre-implantation stage (blastocyst formation) - lasts
first16 days. Shows “all-or-none” effect.
No teratogenesis

2. Period of organogenesis (from 17th to 56th day) -

Drugs may produce
a) no measurable effect;
b) abortion;
c) sublethal gross anatomic defect; or
d) permanent subtle metabolic or functional defect
EFFECT OF DRUGS ON PREGNANCY...

3. 2nd and 3rd trimesters - teratogenicity is unlikely

but drugs can cause retardation of physical or brain
growth, behaviour defect, premature labour, neonatal
toxicity or even post-natal effects like cancer in later life

4. Labour-delivery stage - danger of toxicity in neonatal

period
 Type Of Effects
 Teratogenicity (e.g. thalidomide) - detected at, or shortly after,
birth
 Long term latency (e.g. Diethylstilbestrol - increased risk of
vaginal adenocarcinoma after puberty, or abnormalities in
testicular function & semen production)
 Predisposition to metabolic diseases (e.g. Barker hypothesis -
low birth weight (tobacco smoking) associated with increased
risk of diabetes, hypertension, heart disease in adulthood)
 Impaired intellectual or social development (e.g. exposure to
phenobarbitone- alters programming of brain)
 Malformations
 Overall incidence of
 Major congenital malformations is around 2-3%
 Minor malformations is 9%
 25% are due to genetic or chromosomal abnormalities
 10% due to environmental causes including drugs
 65% of unknown aetiology

 FDA - Part played by drugs is probably small (< 1%)

 Chemical agents / Drugs
 Role of chemical agents & drugs in production of
anomalies is difficult to assess
 Most studies are retrospective
• Relying on mother’s memory
 Large fractions of pharmaceutical drugs used by
pregnant women
• NIH study – 900 drugs taken by pregnant women
– Average of 4/woman during pregnancy
– Only 20% of women use no drugs during pregnancy
 Very few drug categories have been positively
identified as being teratogenic
 Mechanism of action
6 teratogenic mechanisms associated with medication use-

1. Folate antagonism (phenytoin, carbamazepine, valproic acid &

phenobarbital)
2. Neural crest cell disruption (isotretinoin & acitretin)
3. Endocrine disruption
4. Oxidative stress
5. Vascular disruption (Tobacco smoking)
6. Specific receptor- or enzyme-mediated teratogenesis
(Ketoconazole)
Drug prescribing during pregnancy
Drugs may be prescribed for –

i. Treatment of common minor ailments; or

ii. Treatment of pre-existing or pregnancy aggravated

medical illnesses
Treatment of common minor ailment
s
A. Analgesics & antipyretics –
 Paracetamol [Cat B] is safe in normally recommended doses.

B. Nausea & vomiting –

 Meclizine & cyclizine [Cat B] - safe
 Metoclopramide [Cat B] used in labour & during anaesthesia
 Ondensetron [Cat B]

C. Antidiarrheal Medications
 Loperamide [Cat B]
Treatment of common minor ailments...

D. Heartburn & dyspepsia –

 Non-absorbable antacids like aluminium hydroxide [Cat B]
If taken in early pregnancy - ↑ risk of congenital malformations
 Sucralfate [Cat B], H2 blockers [Cat B] are safe
 All PPIs – Cat B except Omeprazole [Cat C]
 Lansoprazole – Safest PPI in pregnancy

E. Constipation –
 Bulk laxatives [Cat B] containing bran, isapghula or
methylcellulose are best for simple constipation
Treatment of common minor ailments...
F. Common cold –
 Antihistaminics (non-sedating - loratadine, fexofenadine &
cetirizine; sedating - chlorpheniramine, diphenhydramine [Cat B])
 Oral decongestants - Pseudoephedrine [Cat B] - risk of gastroschisis
 Loratadine [Cat B]- Possible risk of hypospadias

G. Cough –
 Expectorants – guafenesin [Cat C]
 Antitussives – codeine [Cat C] & dextromethorphan [Cat C]
Treatment of pre-existing or pregnanc
y aggravated medical illnesses
A. Bronchial asthma –
 Short acting beta sympathomimetics – terbutaline [Cat B]
salbutamol [Cat C],
 Long acting beta sympathomimetics – salmeterol [Cat C]
 Inhaled steroids – budesonide [Cat B]
beclomethasone dipropionate [Cat C],
↑ preeclampsia in asthamatic women on oral steroids
 Nedocromil [Cat B] – inhaled anti-inflammatory agent with no
systemic side effects
Treatment of pre-existing or pregnancy aggravated
medical illnesses...

B. CVS diseases –
Hypertension –
 Methyldopa [Cat B] is 1st line drug. S/Es - drowsiness, depression
& postural hypotension
 Beta blockers [Cat C] like atenolol, acebutolol & labetolol
shouldn’t be preferred during first 28 weeks - Fetal bradycardia,
hypoglycemia & possibly fetal growth restriction
 Hypertensive emergencies – hydralazine [Cat C] 5-10 mg IV or
labetolol [Cat C] 20 mg IV
 ACE inhibitors & ARBs [Cat D] – Containdicated
Treatment of pre-existing or pregnancy aggravated
medical illnesses...

 Ca channel blockers - Cat C

• When given during 1st trimester, possibly phalangeal deformities
• When given during 2nd or 3rd trimester, fetal growth restriction

 Diuretics
• Furosemide – Cat C
• Thiazide - Cat D
• Sipronolactone – Cat B
Treatment of pre-existing or pregnancy aggravated
medical illnesses...

 Statins - Cat X
• Should be avoided during pregnancy
– congenital anomalies have been reported

Cardiac arrhythmias–
 Digoxin [Cat C] - maternal atrial flutter or fibrillation
 Quinidine [Cat C] - relatively safe during late pregnancy for
supraventricular tachycardia & some ventricular arrhythmia
 Amiodarone [Cat D] - Should only be given during pregnancy
when there are no alternatives & benefit outweighs risk
Treatment of pre-existing or pregnancy aggravated
medical illnesses...
Anticoagulants –
 Heparin is drug of choice
 Used for management of venous thromboembolism in pregnancy
as they do not cross placenta
 FDA Pregnancy category –
Low molecular weight heparin [Cat B]
Unfractionated heparin [Cat C]

 Warfarin [Cat X/D] - women with mechanical heart valves

who are at high risk for thromboembolis

Thrombolytic agents – Streptokinase [Cat C], urokinase [Cat B] &

t-PA [Cat C] - relatively contraindicated
Treatment of pre-existing or pregnancy aggravated
medical illnesses...
C. CNS diseases –
Epilepsy –
 Women with epilepsy are at ↑ risk of having fetal malformations
even without exposure to anticonvulsant medication
 Phenobarbitone [Cat D] , phenytoin [Cat D] & carbamazepine
[Cat D] may be used
 All three drugs have some side effects as well as birth defects
 Valproate [Cat D] is contraindicated during pregnancy
 All epileptic pregnant women must receive folic acid 5 mg/day
throughout pregnancy to reduce risk of birth defects
Treatment of pre-existing or pregnancy aggravated
medical illnesses...
D. Diabetes mellitus –
 Diet restriction & insulin therapy should be initiated if needed
 Metformin is Cat B
 Oral hypoglycaemics cause fetal hyperinsulinaemia & thus not
used. They also ↑ malformations if taken in early pregnancy

E. Thyroid disorders –
 For thyrotoxicosis, Propylthiouracil is preferred to carbimazole,
due to its greater protein binding capacity
 Although Propylthiouracil associated liver failure in pregnancy
may favour the use of methimazole
 Stable iodine & radioactive iodine [Cat X]
Commonly used drugs and their categorie
s
DRUGS FDA CATEGORY
Analgesics and antipyretics B and C
Acetaminophen B
Aspirin Cat D
Antiemetics B and C
Antibiotics B, C and D
Penicillin,ampicillin,amoxicillin B
Cephalosporin B
Erythromycin B
Gentamycin C
Streptomycin ,Tetracycline D
Metronidazole B
 Commonly used drugs and their categories…
DRUGS FDA CATEGORY
Cotrimoxazole C/D
Quinolones C
Nitrofurantoin B
Antiviral agents B/C
Anti-retroviral agents B/C
Antimalarial C
Antifungal C
Amphotericin B, Terbinafine B
Antitubercular B and C
Vitamin B,C,D,E and folic acid A
Opioids C
Commonly used drugs and their categories…
Drugs FDA Categories
Benzodiazepines D
SSRIs C
Paroxitine D
Tricyclic antidepressants D
Amitriptyline C
Typical antipsychotics C

Atypical antipsychotics C
Clozapine B
Corticosteroids B
Anaesthetic agents B/C
 Vitamin A Analogues
 Isotretinoin [Cat X] - Potent teratogenic
 Severe birth defects
 Cleft palate
Cardiac anomalies
 Neuropsychological impairment – neural tube defects
 Spontaneous abortion
 Premature birth
 Fetal death
 Thalidomide
 Potent Teratogen [Cat X]

 Used for nausea & to alleviate morning sickness in

pregnant women
 Meromelia
 CHD
 Eye abnormalities
 Facial Palsy
 Intestinal atresia
 Many women had taken thalidomide
early in pregnancy

Phocomelia
 Progesterone
 Danazol - Synthetic progestin (but not low doses us
ed in oral contraceptives), when given during first
14 wks - masculinization of female fetus's genitals
 FDA pregnancy category |X|

 Progestin exposure is associated with ↑ prevalence

of cardiovascular abnormalities

 Combined Oral contraceptive pills, when taken

during early stages of unrecognized pregnancy,
are believed to be teratogenic agents.
 Diethylstilbestrol [DES]
 Human teratogen Cat X
 Commonly used in 1940’s & 1950’s to prevent abortion;
in 1971 determined that DES caused ↑ incidence of
vaginal & cervical cancer in women who had been
exposed to DES in utero
 In addition high % suffered from reproductive
dysfunction
 Vaginal adenosis
 Cervical erosions
 Transverse vaginal ridges
 Vaginal adenocarcinoma
 Caffeine
 Whether consuming caffeine in large amounts can
increase perinatal risk is unclear

 Consuming caffeine in small amounts (e.g. 1 cup of

coffee/day) appears to pose little or no risk to the fetus

 Some data, which did not account for tobacco or

alcohol use, suggest that consuming large amounts
increases risk of stillbirths, preterm deliveries,
low birth weight & spontaneous abortions
 Smoking
 Carbon monoxide & nicotine - hypoxia &
vasoconstriction, increasing risk of spontaneous
abortion, fetal growth restriction, abruptio placentae,
placenta previa, premature rupture of membranes,
preterm birth, chorioamnionitis & stillbirth
 Anencephaly, congenital heart defects, orofacial
clefts, sudden infant death syndrome, deficiencies
in physical growth & intelligence & behavioral problems

 Smoking during pregnancy - childhood asthma

 Alcohol
 ↑ risk of spontaneous abortion

 ↓ birth weight by ~1 to 1.3 kg, if regular drinking

 Binge drinking in particular - fetal alcohol syndrome

1. Dysmorphic facial features (all 3 are required) - Small palpe
bral fissures, thin vermilion border & smooth philtrum
2. Prenatal and/or postnatal growth impairment
3. CNS abnormalities (1 required)
a. Structural: head size < 10th percentile, significant brain
abnormality on imaging
b. Neurological
c. Functional: global cognitive or intellectual deficits,
functional deficits in at least three domains
 Cocaine
 vasoconstrictor → hypoxia
 Spontaneous abortion
 Growth retardation
 Microcephaly
 Behavioral problems
 Urogenital anomalies
 Gastroschisis
 Amphetamines
 Pegnancy Cat C

 Defects - Oral clefts, CV abnormalities

Phencyclidine (PCP, angel dust)

 Possible malformations & behavioral disturbances
 Vaccines
 Killed virus, toxoid, or recombinant vaccines may
be given during pregnancy

 Live attenuated vaccines (varicella, MMR & polio)

should be given 3 months before pregnancy or post
partum

 Live virus vaccines are contra-indicated in pregnancy

secondary to potential risk of fetal infection
 Drug of choice
 Hypertension – Alpha methyl dopa
 Hypertensive emergencies – Labetalol
 Hypotension – Ephedrine
 Dibetes mellitus – Insulin
 Hypothyroidism – L-thyroxine
 Hyperthyroidism –
1st trimester – Propylthiouracil
2nd & 3rd trimester – Carbimazole / Methimazole
 Seizures in eclampsia – Magnesium sulphate
Drug of choice...

 Prophylaxis of Malaria – Chloroquine

 P. Vivax Malaria –
1st trimester – Chloroquine
2nd & 3rd trimester – Chloroquine
 P. Falciparum Malaria –
1st trimester – Quinine
2nd & 3rd trimester – Artesunate + Sulfadoxine / Pyrimethamine
 Severe / Complicated Malaria –
1st trimester – Parenteral quinine + Oral quinine + Clindamycin
2nd & 3rd trimester – Parenteral artemisinin derivative followed
by Oral ACT
Drug of choice...

 Induction of labour – Oxytocin

 Ectopic pregnancy – Methotrexate
 Gonococcal infection – Spectinomycin
 Toxoplasmosis – Spiramycin
 Morning sickness – Doxylamine + pyridoxine
 Asthma – Acute attack in pregnancy – Salbutamol
Acute attack in labour – Ipratropium
 Syphilis – Penicillin G
Principles of prescribing during pregnanc
y
 Where possible use nondrug therapy

 Prescribe drugs only when definitely needed

 Choose drug having best safety record over time

 Avoid newer drugs, unless safety is clearly established

 Over-the-counter drugs cannot be assumed to be safe

Principles of prescribing during pregnancy...

 As far as possible, avoid medication in initial 10 wks of

gestation

 Use the lowest effective dose

 Use drugs for the shortest period necessary

 If possible, give drug intermittent

 Conclusion
 Pregnant and lactating women are commonly orphaned
from benefits of drug therapy, even when solid data on
safety/effectiveness exist
 If “Safe use of a drug in pregnancy has not been
established. It should not be administered to women of
childbearing age unless, in opinion of treating
physician, expected benefits to patient markedly
outweigh possible hazards to child or fetus”
 Allow evidence-based counseling
 Always consider risk of untreated maternal condition
 References
 Goodman & Gilman’s The Pharmacological Basis of Therapeutics
12th Edition

 H. L. Sharma & K. K. Sharma’s Principles of Pharmacology

2nd Edition

 Lippincott Illustrated Reviews: Pharmacology 6th Edition

 V. Seshiah, V. Balaji. Insulin therapy during pregnancy. JAPI. July

2007. Vol 55
References...
 Dr. V. M. Motghare. Medication during pregnancy. NOGS.
1996-97. Bulletin 13.

 Punam Sachdeva, B. G. Patel, and B. K. Patel. Drug Use in

Pregnancy; a Point to Ponder! Indian J Pharm Sci. 2009
JanFeb; 71(1): 1–7.

 Drugs During Pregnancy. An Issue of Risk Classification and

Information to Prescribers. Rune Sannerstedt et al. Drug Safety
1996 Feb; 14 (2): 69-77

 Shaikh AK et al. Drugs in pregnancy and lactation. Int J Basic

Clin Pharmacol. 2013 Apr;2(2):130-135