1. TOCOLYSIS & FDA RISK
CATEGORIES
DR RAJEEV SOOD
ASTT.PROF.OBG
IGMC SHIMLA
2. TOCOLYSIS
Preterm labour
• Regular uterine contraction-at least 4 in 20
mts. or 8 in 60 mts. and
• cervical changes – effacement> 80% with
dilatation >=1 cm
• gestation less than 37 completed weeks.
3. DIGITAL EXAMINATION
Cx 80% effaced Cx 80% effaced Cx <80% effaced
dilated >3 cm dilated >1 &<3cm dilated <1cm
Advanced preterm Early Preterm labour
labour
TVS
Cervical Length <2.5 Cervical Length >2.5
cm cm
Threatened Preterm False Labour
4. • Incidence 5- 10 %
• Late preterm births (b/w 34w to 36w 6
d)-74%
• Very preterm (less than32 weeks)
• Perinatal mortality rate in preterm infants
in India is 40 – 150 per 1000 live births.
5. • Preterm birth is associated with a number of
complication in baby
– Asphyxia
– Hypothermia
– Pulmonary syndrome.
– Cerebral haemorage.
– Fetal shock.
– Heart failure.
– Oliguria, anuria
– Infection
– Jaundice
– Anemia
– Retinopathy of prematurity.
6. TOCOLYTIC AGENTS
• Drugs which are used to inhibit uterine
contractions.
• Can be used as
– Short term therapy (1-3days)
– Long term therapy
7. Objectives of short term therapy
• To delay delivery for atleast 24-48 hrs for glucocorticoid
therapy to enhance lung maturation
• In utero transfer of patient to an advanced neonatal
intensive care unit.
Contraindications
Maternal
• Uncontrolled diabetes
• Thyrotoxicosis
• Severe HTN
• Cardiac ds
• Placenta Previa
• Abruption
10. MAGNESIUM SULPHATE
• Acts by competitive inhibition to calcium
ion either at motor end plate or at cell
membrane.
• Decreases acetylcholine release and its
sensitivity at motor end plate.
• Direct depressant action on uterine ms.
11. In addition, MgSO4 has been proposed to
act as neuroprotectant
Following Mechanisms are postulated.
A). Haemodynamic stability
– By stabilizing BP.
– Reducing constriction in cerebral arts.
– Restoring cerebral perfusion.
12. B.
Prevention of excitatory injury and neuronal
stabilisation
↓O 2
Anaerobic metabolism
↓ ATP, ↑ lactic acid
Intracellular accumulation of Na,
Ca, Cl, H2O (Cytotoxic odema)
Excitatory neurotransmitters
(glutamate) released
Ca, Na, influx in post synaptic neurons by
activating NMDA receptors
-Persistent depolarization
13. MgSO4 inhibits this influx and acts as a membrane
stabilizer.
C). Antioxidant Properties
– Increased intracellular Ca inhibits activation of lipases
proteases, endonucleases, phospholipases
– Leads to neuronal cell injury & irreversible brain
damage.
– MgSO4 by blocking Ca Influx reduces the brain
damage.
D). Anti inflammatory properties-
– MgSO4 reduces the synthesis of cytokines and
bacterial endotoxins, minimising the inflammatory
effects of infection.
14. Doses
10 ampoules are dissolved in 500 ml saline
• Loading doses:- 4
gms as slow i/v
Infusion over 20 mts 2 gm in 100 ml
in 100 ml saline.
100 ml/hr
Maintenance doses
• 2 grams /hr- till 12 hrs
1.6 ml in 1 minute
after labour pains
have subsided.
16 drops- 1 ml
25 drops approx. equals to 1.6
ml
25 drops/minute
16. Fetal
• Letharggy
• Hypotonia
• Respiratory depression
• Hypocalcaemia
• Increased frequency of IVH.
Contraindication
• Patients with myasthenia Gravis.
• Impaired renal function
17. β- ADRENERGIC AGONISTS
• Activate intracellular enzymes adenylate
cyclase, cAMP, Protein kinase.
• Reduces intracellular Ca.
• Inhibits activation of MLCK.
• Reduced interaction of actin & myosin- smooth
ms. Relaxation.
• Commonly used drugs are
– Terbutaline
– Ritodrine
– Isoxsuprine
18. Doses
Terbutaline
• 5 mg is dissolved in 500 ml RL (10ug/ml)
• Started at 5 ug/mt (0.5 ml)
• Increased gradually by 5 ug/mt every
10-20 mts until contraction stop or
intolerable side –effects appear.
• Max. dose is 30 ug/mt.
• 0.25 mg every 3-4 hrs sub- cutaneously
can also be given.
19. Ritodrine
• Started by i/v infusion in 5%D.
• 50 ug/mt.
• Increased by 50 ug/mt until cont. stop or toxicity
develops
• Max. dose 350 ug/mt.
• After 12hrs oral therapy with 10-20 mg tab every 4-6 hrs.
Isoxsuprine
• Orally effective long acting selective β stimulant.
• Direct smooth ms. Relaxant property.
Dose
• Initial IV drip 100mg in 5%D .
• Rate o.2ug/min gradually increased to0.8ug /min.
20. • To continue at least 2hrs after contraction
ceases.
• Maintaince-10mg 6hrly /im for 24hrs.
• Oral 10mg 6-8hrly.
21. • SALBUTAMOL-
• IV infusion 5mg in 5%D @10ug/min intially
gradually increased upto50 ug/min .
• Maintainance-4mg tab 6hrly.
• S/E-
tremors,tachycardia,hypertension,palpitati
on.
26. INDO METHACIN
• A cyclo-oxygenase inhibitor
• Reduces synthesis of prostaglandins
leading to decreased intracellular free
calcium
• This reduces activation of myosin light
chain kinase leading to decreased uterine
contractions.
• Loading dose-50 mg orally
• Followed by – 25 mg every 6 hrs for 48
hrs.
27. Side effects
Maternal
• Asthma
• GI Bleeding
• Thrombocytopenia
• Renal Injury
Fetal
• Constriction of ductus arteriosus.
• Decreased fetal urinary output, oligohydroamnios.
• IUGR
• Neomatal Pulmonary HTN.
• Necrotising enterocolitis
• Grade III/IV intraventricular hemorrhage
Contra Indications
• Hepatic ds.
• Active peptic ulcer
• Coagulation disorders
29. • Given as Transdermal patches
• A specific amount of medication is released proportional to the size
of patch.
• Varies B/W 0.1-0.8 mg/hr.
• A low dose patch is started (0.2 mg/hr)
• Add 0.1 mg/hr every hr, if no response.
Intra venous dose
• 100 ug Bolus followed by continuous 1/v infusion at a rate of 1 ug
/Kg/ minute.
Side effects
• Hypotension
• Tachycardia
• Severe headaches
• Methaemoglobinemia
• May causes cervical ripening
30. DIAZOXIDE
• Structurally related to thiazide diuretics
• Inhibits contractility of arterial and venous smooth muscles.
• Also inhibits respiratory, GIT, genitourinary smooth muscle.
Dose
• 5 mg/kg
• 1 ampoule of diazoxide is dissolved in 250 ml of normal saline
• Given slowly i/v over 30 minutes
• Can also be given in boluses of 50-100 mg every 5 minutes
• Patient should be in left recumbent position.
• Continuous monitoring of maternal heart rate, B.P. , Uterine activity
and fetal heart rate is recommended.
To avoid side-effect it is desirable to expand the maternal intra
vascular volume before diazoxide is given.
• 500-1000 ml RL or NS is given.
• Uterine contraction stop within 15 minutes.
• If labour recurs, a second doses can be given.
32. ATOSIBAN
• Oxytocin antagonist
• Blocks myometrial oxytocin receptors.
• Inhibits intracellular calcium release, PG’s release,
inhibiting myometrial contraction.
• Half life is 12 mts
• Crosses placenta but fetal levels are only 10% of
maternal levels.
Doses
• 6.75 mg bolus i/v Injection followed by 300 ug for 3 hrs.
• Maintenance dose of 100 ug/minutes for 48 hrs.
Side-effects
• Nausea
• Vomiting
• Chest Pain
33. ETHYL ALCOHOL
• Inhibitory action on hypothalamus,
preventing release of oxytocin.
• 50ml 95% ethyl alcohol in 450 ml 5% D as
i/v infusion
• Initially7.5ml/kg for first 2 hours followed
by 1.5ml/kg/hr for 10-12hrs .
• Marked maternal CNS depression.
• Risk of foetal hypoxia.
• No longer recommended.
34. ACUTE TOCOLYSIS
• Rapid uterine relaxation is required in following
clinical situations-
• Uterine hypertonus
• Breech delivery
• Intrapartum version of fetal malpresentation
• Shoulder dystocia
• Retained placetna
• Acute uterine inversion
35. Various tocolytics used are
1).Nitroglycerine
– Either sublingual or I/V
– Sublingual- aerosol spray in a dose of 400 ug.
– Intravenous
– 1 amp. Contains 5 mg. This is added to 100 ml of NS
producing a solution of 50ug/ml
For fetal entrapment-200 ug starting dose in given.
Repeated every 2 minutes.
For retained placental or uterine inversion, 100 ug
is given
36. 2). Terbutaline
– 250 ug subcutaneously
– i/V- in 5 ml saline slowly over 5 minutes.
3). Ritrodrine
– 6 mg in 10 ml NS i/V over 3 minutes.
4). Hexoprenaline
– 5 mg in 10 ml NS i/v over 5 minutes.
5.) Atosiban
– 6.75 mg in 5 ml NS i/v over 1 minutes
For malpresentations, third stage complications
Nitroglycerine is drug of choice.
For uterine hypertonus-
– Atosiban terbutaline, ritodrine is preferred.
38. • Risk of major congenital abnormalities in
each pregnancy 2-3%
• 7-10% if minor malformations included.
25% - genetic
2-3%- drug exposure
65% - unknown or combination of genetic &
environmental factors
39. • Teratogen-
Derived from word teratos
Any chemical, virus, environmental
agent, physical factors, drugs.
Act during embryonic or foetal
development to procedure permanent
alteration of form or function.
40. Crieteria for proof of human teratogenecity
are :-
Defect must be completely characterized,
Agent must cross the placenta
Exposure must occur during a critical developmental
period
Biologically plausible association should be there.
Epidemiological findings must be consistent.
Suspected teratogen causes defect in animal
41. Mechanism of teratogenecity
A. Disruption of folic acid metabolism
Responsible for production of
methionine, reqd for methylation
reactions, production of proteins, lipid,
myelin.
42. B. Foetal genetic composition anomalies
can be caused by interaction of
environment & altered genes.
• MTHFR
• Epoxide hydrolase deficiency- leads to
accumulation of oxidative intermediates like
epoxides or arena oxides having carcinogenic &
teratogenic properties.
• Associated with use of phentoin,
carbamazepine, phenobarbitone.
• Transforming growth factor-1 alteration in this
gene causes increased incidence of cleft palate
with smoking.
43. C. Homeobox Genes:- Essential for
establishing positional identity of various
structures along body axis from Brachial
axis to coccyx.
• Retonic acid activates these genes
prematurely resulting in chaoitic
expression.
• Valproic acid alters the expression of Hox
genes.
44. D. Paternal Exposure
Several theories
• Induction of gene mutation or chromosomal
abnormality in sperm
• During intercourse a drug in seminal fluid could
directly contact foetus.
• Paternal germ cell exposure to drugs or
environmental agents may alter gene
expression. eg. mercury, lead solvents,
pesticides hydrocarbons.
45. • Before Day 31- Peri-implantation period all or
none effect conceptus either does not survive or
survives without anomalies.
• Day 31 to 71- embryonic period most cruicial
period.
Period of organogensis.
Effects of teratogen depends on
Amount of drug reaching foetus.
Gestational age at time of exposure.
Duration of exposure.
• After Day71- (Foetal period)
Certain organs remain vulnerable brain
Foetal alcohol syndrome occurs late in pregnancy
46.
47. • Depends on
a)Molecular weight
>1000 Da not cross placenta (Insulin,
Heparin)
c)Concentration of free drug
d)Lipid solubility
e)Uteroplacental Blood flow
f) Placental surface area
g)Placental metabolism
48. DESCRIPTION OF FDA RISK
CATEGORIES OF DRUGS
• A - adequate,well tolerated studies in
pregnant women have no increased risk of
foteal abnormalities
• B – animal studies show no harm to foetus
however there is no adequate and well
controled studies in women or animal
studies have shown adverse effects,but
adequate and well controled studies in
pregnant women have failed to
demonstrate risk to foetus.
49. • C - animal studies have shown adverse
effects and there is no adequate and well
controled studies in pregnant women.or no
animal studies have been conducted and
there are no adequate and well controled
studies in pregnant women.
• D –studies,adequate well controled or
observational ,in pregnant women have
demonstrated risk to the foetus .However
the benefits of therapy may outweigh the
potential risks.
50. • X. – studies adequate well controled or
observational in animals or pregnant
women have demonstrated positive
evidence of foetal abnormalities.The use
of product is contraindicated in women
who are or may become pregnant.
51. Categories of some commonly used
drugs are:-
A. Antihypertensive
Labetalol C
Methyldopa B
Nifedipine C
Amlodipine C
Hydralazine C
Atenolol D
ACE inhibitors C- 1st Trimester
D- 2,3, Trimester
52. B. Anti-Convulsants
Magso4 B
Phenytoin D
Phenobarbitone D
Valproic acid D
Diazepam D
C.Antiemetics
Doxylamine A
Metoclopramide B
Cyclizine/ Meclizine D
53. D.Antibiotics
• Ampicillin B
• Amoxycyline B
• Amoxy-clav B
• Penicillin B
• Cephalosporins B
• Aminoglycosides C
• Ciprofloxacin C
• Doxycycline D
• Levofloxacin C
• Nitrofurantoin B
• Metronidazole B
54. E. Analgesics
• Asprin C
• Ibubrofen B (D in 3rd trimester)
• Mefanamicacid C
• Paracetamol B
• Morphine C
• Pentazocine C
• Pethidine B
55. F. Anti coagulants
• Enoxaparin B
• Heparin C
• Warfarin D
G. Antidiabetics
• Insulin B
• Metformin B
• Gilbenclamide C
57. Teratogenic Drugs With Their Effects
• Alcohol-Foetal alocohol syndrome
Dysmorphic facial features
a) Small palpebral fissures
b) Thin vermillion Borders
c) Smooth philtrum
Prenatal/Postnatal growth Impairment
CNS abnormalities.
