Placenta: Anatomy, Physiology and Transfer of Drugs

Introduction

• The human placenta is a dynamic organ that performs fetal respiration (i.e., oxygenation, carbon dioxide exchange) and waste removal, supports hormonal balance in pregnancy, and helps transport nutrients and medications to or away from the fetus.
• Knowledge of these dynamics remains integral to obstetric anesthesia.

Anatomy

• The human placenta has a hemochorial structure, allowing maternal blood to bathe the placental tissue directly.¹
• Although the sheep model has been used for many placental perfusion and transfer studies, their epitheliochorial placental structure is thicker than that of humans, with three maternal cellular layers separating maternal blood and fetal tissue.
• The embedding of the embryo (blastocyst) in the uterus starts a cascade of developmental changes.

Uterus

• Dilation of local tissue arteries, increasing blood flow
• Vasodilation by replacement of elastic and muscular components of arteries, increasing vessel diameter up to 10 times, and increasing flow.
• Inadequate uterine artery changes result in relative ischemia and intrauterine growth restriction (IUGR)
• The intervillous space holds about 350 ml of maternal blood at term.
• Blood flows from the uterine spiral arteries into the intervillous space, then into the intercotyledons, and finally into the terminal villi, where exchange occurs (Figure 1).
• Umbilical cord arteries (n=2) carry blood from fetus to placenta (de-oxygenated blood).
• Umbilical vein (n=1) carries oxygenated blood from the placenta to the fetus.

Placenta

• Syncytiotrophoblast (invasive edge of placenta) grows into the uterine wall, seeking blood flow.
• Cytotrophoblast proliferation becomes villi, the cauliflower-like appearing part of the placenta where exchange occurs.

• Hypoxia in placental tissue initially helps placental development and angiogenesis.
• Very early in development, the placenta is sensitive to oxygen and reactive oxygen species during organogenesis.
• Abnormal placental development and implantation with decreased vascular development occur as part of early-onset preeclampsia (i.e., clinical development less than 34 weeks of gestation).
• Placental deoxyribonucleic acid (DNA) methylation helps modulate gene expression, and these epigenetic modifications have long-lasting effects on offspring health (e.g., fetal malnutrition and increased cardiovascular disease).

Physiology

• The placenta has many vital functions beyond simple gas and waste exchange, acting as a barrier between maternal and fetal circulations. The placental tissue may absorb, block, or metabolize many endogenous and exogenous compounds.
• Hormonal functions include the production of estrogen, progesterone, human chorionic gonadotropin, and human placental lactogen, among others. These help to maintain and modulate the pregnancy and homeostasis.
• Maternal uterine artery blood flow at term is 10% of the enhanced cardiac output of pregnancy, about 600 ml/minute, with 70-80% directed to the placenta.
• The uterine artery is normally maximally dilated and is part of the low-resistance utero-placental complex; thus, uterine artery flow is dependent on maternal blood pressure. Acute and chronic diseases, as well as vasopressors, can modulate resistance and thus flow.
• The obstetric anesthesia goal of “tight” control of maternal blood pressure (e.g., within 10% of baseline) indirectly helps ensure adequate placental perfusion and fetal gas exchange.
• Fetal blood flow increases over the gestational period via increased vascular growth. The umbilical cord lacks sympathetic innervation to control blood flow, but fetoplacental perfusion is influenced by adrenomedullin, fetal blood pressure, and local autoregulation via nitric oxide. Hypoxia-induced fetoplacental vasoconstriction occurs via decreased nitric oxide, as in hypoxic pulmonary vasoconstriction.
• Several factors influence fetal oxygenation.³ The similarity of maternal uterine vein and fetal umbilical vein PO₂ and PCO₂ suggests a predominantly concurrent blood flow at the terminal villi.⁴
• The placental diffusion capacity of oxygen is low; thus, fetal hemoglobin’s oxygen-binding affinity is an essential driver of fetal oxygenation. Maternal delivery of oxygen (via uterine blood flow) is a key driver of fetal oxygen transfer.
• Fetal hemoglobin has a higher affinity for oxygen with a lower P50 of 18 mmHg, effectively ‘pulling’ oxygen from maternal hemoglobin with a P50 of 27 mmHg.
• In high-altitude pregnancies, the relative chronic hypoxia produces changes that increase the diffusion capacity for oxygen.
• The Bohr effect accounts for 2-8% of oxygen transfer to the fetus, when fetal carbon dioxide transfer to the maternal decreases maternal pH, shifting the maternal/fetal oxygen dissociation curves.
• The healthy placenta has about 50% physiologic “reserve” or tolerance for change in blood flow. The metabolic activity of the placenta takes 40% of maternal uterine oxygen delivery, with the fetus using 0.25 mL/kg/min.⁵
• Carbon dioxide easily diffuses across most biological tissue, including the placenta, with a 20-fold higher diffusion rate compared to oxygen.
• Deoxygenation of maternal hemoglobin increases its affinity for CO₂, facilitating CO₂ transfer from the fetus to the maternal side, a phenomenon called the Haldane effect.
• CO₂ transfer to maternal blood allows more carbonic anhydrase activity, increasing transfer, called the Le Châtelier’s principle.
• The fetal-maternal CO₂ gradient (uterine artery -umbilical vein) is normally only ~ 6 mmHg, while the O₂ gradient is ~60 mmHg, or 10-fold greater at room air.
• The human placenta has several mechanisms for metabolism and transport, and it is itself metabolically very active.
  • Glucose transfer occurs via specific facilitated glucose transporters that are not ATP-dependent.
  • Amino acids are transported via linked translocation of sodium.
  • Free fatty acids cross the placenta by diffusion and fatty acid binding proteins.
  • Active transport consumes ATP in moving against a concentration gradient or eliminating cytotoxic compounds, e.g.P-glycoprotein⁶

Placental Transfer

• The expected fetal exposure to maternal exogenous compounds is influenced by multiple pharmacokinetic and metabolic processes.
• Pharmacokinetic principles that determine whether anesthetic medications typically cross the placenta include molecular size, pKa, lipid solubility, protein binding (albumin vs. alpha1-acid glycoprotein), and tissue binding.
• Large, charged molecules typically do not cross the placenta to a clinically significant extent. See Table.
• Dexmedetomidine has become used more often in obstetric anesthesia, for the quality of pain relief (e.g., pain during cesarean section) and for shivering during cesarean.7 Although the Fetal/Maternal blood ratio is only 0.12, there may be significant binding in placental tissue. In addition, the strong alpha2-adrenergic agonism may increase uterine tone and/or contraction frequency at higher clinical doses.⁸
• Vasopressors may cross the placenta and affect fetal condition in addition to effects on maternal perfusion of the uterus. Ephedrine crosses the placenta and may increase fetal metabolism, resulting in a slightly lower pH, whereas phenylephrine and norepinephrine do not cross the placenta in humans at cesarean delivery.⁹
• Fetal levels of local anesthetics and some opioids may increase during periods of fetal acidemia. Neutral molecules cross the placenta more easily and exist in equilibrium between maternal and fetal circulations.
• Fetal acidemia will convert the weak bases (e.g. lidocaine, bupivacaine, fentanyl) to their ionized form, thus pulling more drug across the placenta in neutral form – termed “ion trapping.”^1,10

Clinical Implications

• Meperidine was used for labor analgesia many years ago, but produced neonatal depression, especially during the peak blood level and placental transfer of the active metabolite normeperidine. Meperidine is still useful for shivering after delivery.
• Neuromuscular blockade reversal with the cholinesterase inhibitor neostigmine should be used with the anticholinergic atropine to avoid possible fetal bradycardia
• Fetal acidemia may increase maternal to fetal drug transfer via ‘ion trapping’ (e.g., lidocaine, bupivacaine, fentanyl).
• Ephedrine may cross the placenta and increase fetal heart rate, especially at medium-higher doses (e.g., more than 25 mg IV).