FETAL CIRCULATION
AND
PLACENTAL TRANSFER OF DRUGS &
ANAESTHETIC AGENTS
Speaker : Dr Sabari Kreeshan,
DNB Resident, Anaesthesia Dept.
Moderator : Dr Surinder ,
Consultant, Anaesthesia Dept.
Govt. Hospital, Gandhi Nagar
Jammu.

Contents
 Fetal circulation
 Transitional circulation
 Placental anatomy
 Mechanism and factors affecting transport
 Transfer of respiratory gases
 Drug transfer

FETAL CIRCULATION
Umbilical
artery
placenta
Umbilical vein
( PaO2 – 32 mmHg)
( SaO2- 80 -85 %)

Liver Hepatic
Circulation
Inferior Vena Cava
PO2 – 26-30 mmHg
SaO2 – 65-70%
Ductus Venosus
(40-60 %)
Hepatic Vein
(PaO2-27 mmHg
SaO2-65%)
Lower body
(PaO2 10-12mmHg)
SaO2 35%

PREFERENTIAL FLOW
STREAMING
66%
34%
Highly oxygenated
blood to brain
Combined
Ventricular
output
(PARALLEL
CIRCULATION)
SaO2
40%
SaO2
65-70%
saO2
60-65%
SaO2
50-55%
-SaO2
55-60%

FETAL OXYGEN TRANSPORT
• Hb concentration >18 g/dl
• At term HbF approx 75%-84% of total Hb,
between 6-12 months fetal Hb → adult Hb
• P50 is 27mmHg for adult Hb, 19-21mmHg for fetal Hb
 HbF – 2 α and 2 γ chains
 2,3-DPG stabilizes deoxygenated Hb tetramer - ↓ O2
affinity
 γ chains donot readily bind to 2,3- DPG – Higher O2
affinity of HbF
 6-8% higher saturation on fetal side of membrane

OXYHEMOGLOBIN SATURATION CURVES
Fetal Hb ODC is to the left of
Adult Hb ODC

Fetal Circulation

UMBILICAL CORD CLAMPING
EXPOSURE TO ROOM AIR
TRANSITIONAL CIRCULATION
↓↓PVR
↑ SVR
↑ PULMONARY
BLOOD FLOW
↑ OXYGENATION
RESPONDS TO CHANGES IN PaO2, PaCO2, pH & CIRCULATING FACTORS
SVR – systemic vascular resistance PVR – pulmonary vascular resistance
↑ SVR ↓PVR
MECHANICAL INFLATION OF LUNGS
(↑ alveolar O2 tension,↑PaO2,↓PaCO2)
EDRF & PGs
↑ LT. ATRIAL FLOW
↓FORAMEN OVALE
SHUNT
F.O. CLOSURE
DUCTUS
ARTERIOSUS
CONSTRICTION

Transitional & Neonatal Circulation
 PVR & PAP continue to fall over the next 2-3 years
 Decrease in PVR (80%) - first 24 hours & PAP falls
below systemic pressure in normal infants
 Babies delivered by C-section have a higher PVR than
those born vaginally which reaches normal range 3
hours after birth

Transitional & Neonatal Circulation
The pulmonary vasculature of the newborn can
respond to chemical mediators such as
Histamine
Acetylcholine
Prostaglandins
**All are vasodilators
Hypoxia, acidosis,hypercarbia and surgical
stimulation can reverse this causing severe
pulmonary constriction

Ductus Arteriosus
Functional closure- 10-15 hours after birth
( reversible in hypoxemia and hypovolemia)
Permanent closure 2-3 weeks
Remnant ligamentum arteriosum

Foramen Ovale
 Increased pulmonary blood flow & left atrial
distention cause closure
 Functional closure- at birth ,
anatomical closure – by 1 year
 maneuvers increase PVR increases RA & RV
pressure
 Right to left atrial shunt may occur in newborns
& young infants

Placental transfer of drugs and
Anaesthetic agents

Placental anatomy and circulation
villous hemochorial type

Structure of chorionic villus Cross section of villus

Fetal – Contained within vessels
• Umbilical Arteries →chorionic plate → branches to
stem villi → capillaries in terminal villi → return via
umbilical vein
Maternal – Free-flowing lake
• uterine artery → spiral artery in basal plate
• Spiral arteries open into intervillous space bathing
the villi (under arterial pressure) → towards
chorionic plate (passing fetal villi) → veins in basal
plate

MODES OF TRANSFER ACROSS PLACENTA
1. DIFFUSION
WATER,
LIPOPHILIC MOL
GLUCOSE
AMINOACIDS

2. ACTIVE TRANSPORT
Primary active transport Secondary active transport
Eg. Sodium potassium pump
calcium pump
Eg. Water soluble vitamins
calcium , magnesium

3. BULK FLOW
• due to hydrostatic or osmotic gradient
• water movement depends upon sodium chloride
pumping thus ATP dependant
• Hypoxia diminishes ATP
4. BREAKS
• Delicate villi break in intervillous space extruding
contents in maternal circulation .
• eg alloimmunization and erythroblastosis fetalis

5. PINOCYTOSIS
Eg : Ig G, iron

FICK PRINCIPLE: rate of drug transfer
Q/t = K X A X ( Cm – Cf )
D
Q/t – rate of diffusion
K – diffusion coeff
A – surface area of membrane
Cm,Cf – maternal and fetal conc
D – thickness of membrane

Factors Affecting Placental Transfer
Drug Factors
1. Protein binding – highly protein bound drugs are
affected by the concentration of maternal and fetal
plasma proteins which varies with gestational age
and disease
• Albumin (lower binding affinity) increased transfer
of drugs
• Alpha-1-acid glycoprotein (higher binding affinity)
decreased transfer of drugs

2. Degree of ionization
Henderson- Hasselbalch equation
pH = pKa + log [ base ]
[ acid ]
• In pregnancy -pH gradient between mother and
fetus – fetal acidemia enhances the maternal to
fetal transfer (ie “ ion-trapping” ) of basic drugs eg
local anaesthetics and opioids

3. Lipid solubility
4. Charge of molecule (scoline highly ionized,
thiopentone relatively nonionized )
5. Size – molecular weight ( heparin 6000 Da, warfarin
330 Da)
6. Altered pharmacokinetics – altered volume of
distribution of drugs due to increased TBW ,
progressive depression of hepatic microsomal
enzymes increases the elimination t1/2

Fetal factors
1. Fetal circulation
Differential regional
distribution of blood
in fetus
Maximum drug conc
in liver
Detoxification
Redistribution of blood
flow
Hypoxia ,
intrauterine
stress
Higher drug conc
to vital organs

2. Metabolic capacity
metabolic enzymes in liver like glucouronyl
transferase are immature leading to increased t ½
3. Relatively deficient CNS myelination

 Maternal factors
1. Drug concentration in maternal blood
2. Maternal blood flow
• ↓ perfusion - ↓placental flow - less drug transfer
(hypotension, or aortocaval compression)
• better placental function in LSCS - larger doses to
reach fetus - minimal effective dose should be used
• Disease states alter placental transport (pre-
eclampsia)

Placental factors
1. Placental binding
2. Placental metabolism
3. Diffusion capacity
4. Gestational age ( placenta is more permeable in
early pregnancy )
5. Area of placenta -↓ in abruptio placentae, maternal
hypertension, intrauterine infections, congenital
defects however large placenta in erythroblastosis
is hydropic does not ↑ transfer

UTERINE BLOOD FLOW
• UBF =uterine arterial pressure – uterine venous pressure
uterine vascular resistance
• no autoregulation
• factors ↓ UBF
1. ↑ uterine venous pressure
 Uterine contractions
 Abruptio placentae
 Oxytocin overstimulation

2. ↓ uterine arterial pressure
 Sympathetic block
 Hypovolemic shock
 Supine hypotensive syndrome
3. ↑ uterine vascular resistance
 Essential hypertension
 Pre – eclampsia
 Sympathetic discharge
 Adrenal medullary activity
 Sympathomimetic drugs except ephedrine

UMBILICAL BLOOD FLOW
• At term 120ml/kg/min or 360 ml/min
• unaffected by moderate hypoxia but ↓ by severe
hypoxia
• umbilical blood flow decreases with catecholamines
and cord occlusion
• lateral or trendelenburg position can relieve cord
compression

TRANSFER OF RESPIRATORY GASES
OXYGEN TRANSPORT
• Placenta – 1/5 of the oxygen transfer efficiency of
the adult lung
• 8ml O2/min per kg fetal body weight for growth and
development .
• Oxygen transfer depends upon partial pressure
gradient

• Factors favoring transport
1. Difference in ODC – fetal ODC is to the left of
maternal ODC enhancing O2 uptake by fetal RBC
2. Double Bohr effect – fetal CO2 transfer makes
maternal blood acidic and fetal blood alkalotic
causing right and left shift of respective ODC

CARBON DI OXIDE TRANSPORT
• Mainly HCO3 ͞ (62%), dissolved CO2 (8%)
• Factors favoring fetal to maternal transfer
1. fetal pCO2 - 40 mmHg and maternal pCO2 - 34mmHg
2. La Chatelier’s principle- fetal to maternal CO2
movement causes shift in equilibrium of carbonic
anhydrase reaction producing more CO2 for
diffusion
3. Haldane effect- deoxyHb in maternal blood has
higher affinity for CO2

DRUG TRANSFER
Total drug dose to infant = Maternal concentration X F: M
ratio of drug
F:M Ratio = umbilical Vein Vs maternal venous
concentration

INHALATIONAL AGENTS
Rapid transfer
low molecular weight
lipid soluble
+
prolonged induction
to delivery time
Rapid transfer
•During GA-N2O, volatile
agents ↑ in fetal
circulation & prolonged
delivery → neonatal
depression

• Induction to delivery interval – 8-10 mins
→ high inspired O2 maintained & aorto –
caval compression avoided
• U-D interval › 90 secs – fetal asphyxia ,
acidosis apparent
 partial placental separation
 premature fetal resp efforts
 impaired placental blood flow

INHALATIONAL AGENTS
DRUG TRANSFER F:M
HALOTHANE BRISK (<1 MIN) 0.71 to 0.87
(›2 MAC ↓UBF )
ISOLFLURANE RAPID 0.7
DESFLURANE/
SEVOFLURANE
?RAPID NO STUDIES
NITROUS OXIDE RAPID 0.83(3 min exposure)
NITROUS OXIDE:RAPIDLY CROSSES PLACENTA
• DIFFUSION HYPOXIA IN FETUS
•PRUDENT TO OXYGENATE NEONATES WITH INTRA UTERINE EXPOSURE

INTRAVENOUS AGENTS
AGENT F:M CLINICAL IMPLICATIONS
THIOPENTONE 0.4 to 1.1 Freely diffusible
Marked decrease in
placental BF
Popular agent of choice
PROPOFOL 0.65 to 0.85(bolus 2 to
2.5 mg/kg)
0.50 to 0.54 (inf @ 6-9
mg/kg/hr)
FDA – category B drug
Sedative effect on
neonate
Lower 1 and 5 min apgar
scores (2.8 mg/kg)
UBF no change
KETAMINE
ETOMIDATE
1.26( in 1.5 min) Rapidly crosses placenta
Used in hypotension and
asthma
0.5 Used in hemodynamic
instability

BENZODIAZEPINES
AGENT F:M REMARKS
DIAZEPAM 1 Loss of baseline
variability of FHR
Dose dependent
hypotonia
(FLOPPY INFANT)
Depression of temp.
regulating system
immature infants)
MIDAZOLAM 0.76(within 20 min
levels fall quickly)

OPIOIDS
DRUGS F:M REMARKS
MORPHINE 0.6 Resp.depression &
acidosis
Max: 2.5 -3hrs
Loss of baseline
variability of FHR
Impaired acid-base
balance
Impaired
neurobehavioral
responses
PETHIDINE <1 (Neonatal depression
longer than
pentazocine)
PENTAZOCINE < pethidine
FENTANYL 0.37 to 0.57
SUFENTANIL 0.81 >maternal prot binding
ALFENTANIL 0.3 ↓ 1 min apgar score
REMIFENTANIL 0.88 No adverse neonatal
effects

LOCAL ANAESTHETICS
Transfer across placenta depends upon
• pKa – degree of ionization at a particular pH
• fetal acidemia enhances the maternal to fetal
transfer (ie “ ion-trapping” )

LOCAL ANESTHETICS
AGENT F:M PROTEIN BINDING
BUPIVACAINE 0.3 90%(α1 acid
glycoprotein)
LIGNOCAINE 0.55 (20% bound to
maternal protein)
ROPIVACAINE 0.2 90-95% protein
bound

OTHER DRUGS
• MUSCLE RELAXANTS:
Quaternary ammonium salts
Do not readily cross placenta
Succinylcholine – F:M=0
Vecuronium – 0.06-0.11
Rocuronium – 0.06
Atracurium − 0.07
• ANTICHOLINERGICS:
Atropine (0.93)
Glycopyrrolate (0.22) poorly crosses placenta

Other drugs……..
• ANTICHOLINESTERASES:
• Quaternary ammonium compounds
• Limited placental transfer
Neostigmine + Glycopyrrolate= fetal bradycardia
Hence, neostigmine + atropine is preferred!!!!!!!

ANTI- HYPERTENSIVES
Β- BLOCKER F:M REMARKS
ATENOLOL 0.9 IUGR
Neonatal
bradycardia
Hypoglycemia
Resp.depression
METOPROLOL 1
LABETALOL 0.3
PROPRANOLOL 0.26 ( 3hrs prior)
1.0 ( long term )
LABETALOL - AGENT OF CHOICE IN PREGNANCY

ESMOLOL 0.2 Fetal Bradycardia
CLONIDINE 0.89 Significant ↓UBF ,
fetal hypoxia (300μg
iv )
DEXMEDETOMIDINE
0.12 ▬
PHENOXYBENZAMINE
(pheochromocytoma)
1.6 ▬
HYDRALAZINE 1.0 Fetal vasodilatation
NITROGLYCERINE 0.18 Minimal changes in
fetal UBF , PR , BP
ACE –INHIBITORS ▬ Alter fetal renal
function

VASOPRESSORS
• Ephedrine crosses placenta- F:M- 0.7
• Ephedrine and phenylephrine – venoconstriction
→improves VR → ↑cardiac output restores
uterine perfusion
• Phenylephrine (α agonist )- mesentric Vc
→↑cardiac preload improves utero-placental
circulation

Phenylephrine better
ephedrine ( β-agonist mostly)
↓
readily crosses placenta
↓
fetal β adr stimulation
↑fetal catecholamine levels
↑ FHR & oxygen consumption
↓
fetal acidosis

Other drugs:
ANTICOAGULANTS:
Warfarin:
• No F:M ratio is measured
• Fetal loss & congenital anomalies
Heparin:
• does not cross placenta (even at conc. Used in Ac.
Thromboembolism)
• LMWH, Enoxaparin, Fondaparinux- no placental
transfer ( in vitro studies )
ANTICOAGULANT OF CHOICE IN PREGNANCY

• Newer drug delivery systems alter drug transfer and
distribution eg liposome encapsulation of valproic
acid
• Disease states affect transfer – glyburide lower F/M
ratio 0.3

Drugs crossing placenta
Anticholinergics
• Atropine
• Scopolamine
Antihypertensive agents
• Beta-adrenergic receptor antagonists
• Nitroprusside
• Nitroglycerine
Benzodiazepines
• Diazepam
• Midazolam
Induction Agents
• Propofol
• Thiopentone

Inhalational anaesthetic Agents
• Halothane
• Isoflurane
• Nitrous oxide
Local Anaesthetics
Opioids
Vasopressors
• Ephedrine

Drugs that Do Not Cross the Placenta
Anticholinergic
• Glycopyrrolate
Anticoagulants
• Heparin
Muscle Relaxants
• Depolarizing – succinylcholine
• NDMRs

References
• Miller’s text book of anaesthesia, 7th edition
• A practice of anaesthesia, wylie, 7th edition.
• Clinical anesthesiology, Morgan, Mikhail, Murray,
4th edition

Thank You