FETAL CIRCULATION AND PLACENTAL TRANSFER OF DRUGS & ANAESTHETIC AGENTS Speaker : Dr Swati Bansal Moderator : Dr Priyanka Khurana University College of Medical Sciences & GTB Hospital, Delhi email: anaesthesia.co.in@gmail.com www.anaesthesia.co.in

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

FETAL CIRCULATION ( PaO2 – 32 mmHg) 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%

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

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

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

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

3. BULK FLOW 4. BREAKS 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 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

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 Hypoxia , intrauterine stress Differential regional distribution of blood in fetus Redistribution of blood flow Maximum drug conc in liver Higher drug conc to vital organs Detoxification

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

Maternal factors Drug concentration in maternal blood 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 Placental binding Placental metabolism Diffusion capacity Gestational age ( placenta is more permeable in early pregnancy ) 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 ↑ uterine venous pressure Uterine contractions Abruptio placentae Oxytocin overstimulation

↓ uterine arterial pressure Sympathetic block Hypovolemic shock Supine hypotensive syndrome ↑ 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 Difference in ODC – fetal ODC is to the left of maternal ODC enhancing O2 uptake by fetal RBC 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 fetal pCO2 - 40 mmHg and maternal pCO2 - 34mmHg La Chatelier’s principle- fetal to maternal CO2 movement causes shift in equilibrium of carbonic anhydrase reaction producing more CO2 for diffusion Haldane effect- deoxyHb in maternal blood has higher affinity for CO2

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

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

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 (›2 MAC ↓UBF ) 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 0.83(3 min exposure) NITROUS OXIDE:RAPIDLY CROSSES PLACENTA DIFFUSION HYPOXIA IN FETUS PRUDENT TO OXYGENATE NEONATES WITH INTRA UTERINE EXPOSURE

CLINICAL IMPLICATIONS 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 Used in hemodynamic instability 0.5

0.76(within 20 min levels fall quickly) 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 90%(α1 acid glycoprotein) 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 CLONIDINE 0.89 DEXMEDETOMIDINE 0.12 HYDRALAZINE 1.0 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: ANTICOAGULANT OF CHOICE IN PREGNANCY 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 Obstetric anesthesia- Principles & practice- 4th edition. David H Chestnut Shnider and Levinson′s Anesthesia for Obstetrics Miller’s text book of anaesthesia, 7th edition A practice of anaesthesia, wylie, 7th edition. Clinical anesthesiology, Morgan, Mikhail, Murray, 4th edition Textbook of Obstetrics- D.C Dutta Essential Pediatrics- O P Ghai- 6th edition

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