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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.52 no.1 Campinas Jan./Feb. 2002
Placental transfer and embryo-fetal effects of drugs used in anesthesia *
Pasaje transplacentária y efectos embriofetales de drogas usadas en anestesia
Márcio Leal Horta, TSAI; Ione Pellegatti LemonicaII
IProfessor Titular da Universidade
Católica de Pelotas, Mestre em Anestesiologia e Doutorando do Departamento
de Anestesiologia da Faculdade de Medicina de Botucatu, UNESP
IIDoutora em Farmacologia, Especialista em Toxicologia da Reprodução, Docente do Curso de Pós-Graduação em Anestesiologia da Faculdade de Medicina de Botucatu, UNESP
BACKGROUND AND OBJECTIVES: Anesthesia
for pregnant patients has several peculiarities that need to be adequately analyzed.
Besides fetus exposure and possible toxic effects of anesthetic agents, gestational
age, drug properties and doses should be considered. The lack of adequate information
about the risk of using drugs during gestation turns it difficult for anesthesiologists
to make a safe choice when facing the need to anesthetize a pregnant patient,
both for non-obstetric or for obstetric surgery. In the former case, it is important
to avoid premature labor (or abortion) and permanent fetus abnormalities; in
the latter, there should be neither interference on uterine contractility nor
significant fetus depression. This review aimed at updating information on placental
transfer of anesthetic drugs and maternal-fetal effects of anesthetic drugs.
CONTENTS: The mechanisms of placental transfer of drugs and the basic principles of embryo-fetotoxicity are reviewed and important aspects of embryo-fetal effects of anesthetic drugs are analyzed. FDAs classification of drugs most frequently used in anesthesia is presented, according to their teratogenic risk.
CONCLUSIONS: There are still many issues involving the choice of anesthetic drugs to be used in pregnant patients, but today there are new drugs and information allowing anesthesiologists to grant greater security to both mother and fetus.
Key Words: COMPLICATIONS: teratogenicity; DRUGS: embryo-fetal effects; PHYSIOLOGY: placental
JUSTIFICATIVA Y OBJETIVOS: La anestesia
de la paciente embarazada engloba diversas situaciones que deben ser analizadas
con mucha propiedad. Además de la exposición del feto y de una posible
acción tóxica de los agentes que serán utilizados en la anestesia,
deben ser considerados el período gestacional, las características
de cada droga y las dosis que serán utilizadas. La falta de informaciones
adecuadas sobre el riesgo del uso de drogas en la gestación torna difícil
al anestesista una opción segura cuando se ve delante de la necesidad de
anestesiar una paciente embarazada, tanto para cirugía no obstétrica,
como en cirugía obstétrica. En el primer caso, es importante evitar
el parto prematuro (o aborto) y el aparecimiento de alteraciones permanentes
en el feto. En el segundo caso, no debe haber interferencia en la contratilidad
uterina ni depresión significativa en el feto. La finalidad de esta revisión
es actualizar los conocimientos sobre el pasaje transplacentaria y los efectos
maternofetales de las drogas usadas en anestesia.
CONTENIDO: Son revisados los mecanismos de pasaje transplacentaria de drogas, los principios fundamentales de embriofetotoxicidad y analizados algunos aspectos importantes sobre efectos embriofetales de las drogas utilizadas en la anestesia. También se presenta la clasificación de riesgo teratogénico, de acuerdo con el FDA, de las drogas que el anestesista utiliza más durante el acto anestésico.
CONCLUSIONES: No obstante aún persistan muchas dudas en relación a la selección de drogas para la anestesia de pacientes embarazadas, el anestesista hoy dispone de nuevas drogas y de informaciones que le permiten ofrecer mayor seguridad para el binomio madre-feto.
The lack of information on the use of drugs during gestation and insufficient data in humans often lead to the non recommendation of their use during pregnancy 1. If on one side, such recommendation aims at bringing more safety to mother and fetus, on the other, it makes difficult to the professional a criterious and unbiased judgment of the risk-benefit ratio of administering drugs to pregnant patients.
This is especially important for anesthesiologists dealing with non-obstetric surgeries which, by themselves, imply maternal-fetal risks and may impair the evaluation of results 2.
Two aspects of inhalational anesthetics should be highlighted: the first is that experimental exposures in general do not reflect human exposure reality which tends to be unique in high doses and a short period of time; the second has to do with the surgical staff, exposed to low concentrations but for very long and repeated periods, especially in the absence of a good expired gases scavenging system.
There are extensive reviews on the subject 3-5, but the introduction of new drugs and new information about existing ones call for knowledge updates. Current knowledge about maternal/placental/fetal transfer and about the risks of using drugs in pregnant patients is reviewed in this article, with a major focus in anesthetic drugs. A classification of their embryo-fetotoxic risk is also presented.
PLACENTAL TRANSFER OF DRUGS
The eggs viviparous animals are poor in nutrients and develop inside the maternal body. This implies deep changes in the mother to establish a transfer pathway between mother and fetus, able to transfer to the latter all nutrients needed for its adequate development as well as to eliminate metabolic residues. After a short initial transfer period by diffusion between the egg and tube and uterine secretions, this fundamental function is performed by the placenta through which one may say that, respected the pharmacokinetic principles, what circulates in the mother is transferred to the fetus.
In analyzing maternal-fetal transfers, three fundamental elements must be considered: fetus, amniotic compartment and placenta. Although amniotic fluid dynamics is very intense (it is estimated that its total volume can be renewed in approximately 3 hours) 6, and although it may accumulate substances produced in the placenta, as it is the case of POEF (Plasma Opioid Enhancing Factor), responsible for the exacerbation of opioid effects in experimental studies in rats ingesting amniotic fluid 7, it seems that the amniotic fluid is not so important when anesthetic agents are concerned. For example, fentanyl administered to women between 8 and 14 weeks of gestation was detected in the placenta and fetal brain, but not in the amniotic fluid 8.
Term human placenta weighs approximately 500 g and the uterine-placental blood flow at this time is of approximately 600 ml.min-1. Maternal-fetal transfers are accomplished between placental villi (fetus) and intervillous spaces (mother). Between intervillous spaces and fetal capillaries there is the placental membrane, constituted of syncytiotrophoblast, cytotrophoblast and connective tissue 9.
There are several mechanisms responsible for drug transfer through the placental membrane:
Simple passive diffusion is the most common process of drug transfer through membranes, which only depends on a concentration gradient and does not involve energy waste or the presence of carriers. Through this process, oxygen, CO2, sodium, chloride and fatty acids cross the placenta, as well as most molecules with molecular weight below 600 and membrane crossing physical-chemical properties. Simple diffusion placental crossing follows FICKs law, represented by the following formula:
Q/t = Diffusion speed.
K = Drug diffusion constant. The highest the drug liposolubility and the lowest the protein binding, ionization (which depends on drugs pKa and mother and fetus pH) and molecular weight, the highest the diffusion constant.
A = Placental surface area. The placenta measures 10 to 15 m2 and its functional area is of approximately 1.8 m2. This area is decreased in the presence of abruptio placentae, placental infarction, hypertension (fibrosis) and intra-uterine infection. Placenta is increased with diabetes, which may explain a further fetal development by increased nutrients transfer. There is also placental increase with fetal erythroblastosis, but in this case placenta is hydropic, thus functionally impaired.
Cm = Maternal concentration. In addition to the dose, all factors accelerating drug absorption or decreasing its metabolism or excretion will contribute for high maternal concentration and, as a consequence, for higher maternal-fetal gradient.
Cf = Fetal concentration. Part of the blood returning by the umbilical vein goes through the ductus venosus without crossing the liver and decreases the possibility of first passage metabolism, thus increasing drug bioavailability. In addition, fetal liver has a limited metabolization ability. These two factors are important for making easier the increase of drug concentration in fetal bood and interfering in the establishment of a maternal fetal gradient. Other factors, such as pH changes, may also impact this process.
D = Membrane thickness. Placental membrane is made up of cell layers and connective tissue, which make it thick. This thickness tends to decrease with time, being approximately 25 µ in the beginning of gestation and 2 to 6 µ (mean 3.7 µ) at birth 8. Drug transfer is progressively easier as pregnancy progresses to help meet increasing needs of a body in fast development. However, from the 36th week, there is a decrease in patency 3, indicating the beginning of aging of the organ.
Facilitated diffusion is another placental membrane diffusion process where there is no energy waste. This process, however, needs a carrier to make the transfer more efficient. This is the mechanism through which glucose or lactic acid molecules cross the placenta.
Active transportation through the membrane is a less frequent mechanism, but is responsible for the transfer of very important substances. This type of transportation involves energy wasting and is independent of the concentration gradient. Large ions, such as calcium and iron, aminoacids and vitamins A and C are transported by this mechanism.
Water, which may carry some solutes, is transferred by simple membrane filtration process.
Pinocytosis is a process that takes place with large molecules such as immunoglobulines. It is the mechanism through which maternal antibodies are transferred to the fetus and explains the maternal-fetal transfer of immunization, a beneficial process in case of antibodies against diseases, and malefic if the transfer is of anti-Rh antibodies.
SOLUTIONS OF CONTINUITY
Solutions of continuity allow for the transfer of fetal blood to the mother, leading to the formation of anti-Rh antibodies in a Rh negative mother with an Rh positive baby.
Other factors interfering in the general transfer mechanisms described above should be considered.
Placental (fetal) and Intervillous (maternal) Blood Flows - They depend, among other factors, on blood pressure and contractile status of vessels on both sides of membrane. Constriction of placental vessels determines a decrease in perfusion and maternal-fetal transfers.
Flow Decrease in Patency Areas - There may be flow changes in areas of greater patency leading to a dysfunction in transfer mechanisms, similar to what happens to the lungs when ventilation/perfusion ratio is changed.
Binding or not to Molecules - When drug concentrations in compartments are evaluated, data refer to total concentration. However, the balance between both membrane sides, determined by the diffusion process, is solely dependent on the liposoluble fraction. Protein bound, ionized and tissue-bound fractions do not affect such balance, thus allowing total drug concentration in each membrane side to be completely different. This may mimic differences in drug ability to cross the placenta and may also result in problems because neonate pH changes may determine an increase in drugs free fraction with a consequent increase in effects and even intoxication.
Flow Sense - Concurrent and countercurrent flow systems coexist in the placenta. Countercurrent flow system, similar to what happens in the kidneys, is far more efficient than concurrent systems to transfer substances.
Placental Metabolism - Oxygen is consumed by trophoblasts and its transfer seems to be less efficient when umbilical oxygen tensions are analyzed. There may also be consumption or metabolism of other elements, mimicking poorer transplacental transfer efficiency.
Pressure Difference - In addition to FICKs law-related aspects, placenta crossing is also affected by the difference in pressure between both membrane sides. On the maternal side, placental pressure is approximately 70 to 80 mmHg and 8 mmHg in venous territory. Intervillous space pressure in the uterus at rest is 5 to 8 mmHg and may increase in labor to 30 to 50 mmHg during contractions and to 8 to 12 mmHg in the intervals. On the fetal side, umbilical artery pressure is 50 mmHg and venous pressure is 25 mmHg. Fetal capillary pressure, estimated in approximately 30 mmHg, is higher than that of the maternal side. Since the pressure gradient tends to be in the fetal-mother sense, during placental solutions of continuity the transfer occurs mainly in this sense, thus explaining the iso-imunization process by Rh factor. The trend is always the mother receiving fetal blood and producing antibodies which eventually will be transferred to the fetus by pinocytosis 6.
INTRAUTERINE EXPOSURE TO CHEMICALS
In evaluating pregnant women exposure to any type of chemicals (among which anesthetic drugs), one should not only consider the maternal effects but also the effects on a new unit, called maternal-placental-fetal unit. So, the use of drugs, as well as pharmacological and toxicological tests performed before their commercialization, should consider the new existing kinetic conditions in the pregnant body - primary target for such substances - and their potential actions on the embryo-fetal organism 10.
Several variables should be evaluated during gestation to determine the action of chemical substances. Experimental animals may show a different sensitivity when exposed to the same chemical and such sensitivity may be different from that shown by humans. Since in teratogenesis it is impossible to perform human experiences, results of animal tests are extrapolated to humans. Generally, it is admitted that humans are more sensitive to chemicals than lab animals. This is why, for the commercialization of a new drug, safety indices are applied to determine safe doses for human utilization of a drug tested in animals.
In addition to placental crossing, which is different depending on the gestational age, intrauterine exposure may cause different final manifestations of abnormal fetus development, depending on the gestational age when it occurred. So, embryonary exposure during the first two weeks will find a fetus with indifferentiated totipotent cells which may be replaced by normal cells in case of chemical injury. As a consequence, and depending on the number of injured cells, there will be the development of a normal individual (in the presence of conditions for the injured cells to be replaced) or early embryonic death and abortion (if a large number of cells are injured without possibility of replacement).
After this initial gestation period, there is a period characterized by an intense cell proliferation and differentiation when all embryonary organs and systems are formed. It is only in this period that one may state that any change in the embryos normal development may result in fetal malformations. In men, the period of highest embryonic sensitivity to chemical agents goes from the 17th to the 60th day of gestation. However, considering individual differences as to major events of gestation, the first three months of human gestation are considered the period of highest sensitivity.
This period is followed by the fetal period during which intrauterine exposure to chemicals no longer results in malformations, but may interfere with fetal growth and/or the development of previously formed systems, among them the central nervous system. Final manifestations of development delays and newborn functional abnormalities may be consequences of such exposure.
Another parameter to be considered when evaluating intrauterine exposure to chemicals and possible fetal effects is the dose. It is now known that for all chemical agents there are limits below which the drug may be safely administered and above which toxic effects on the embryo-fetal organism start to be seen 10.
All these considerations indicate that each pregnant patient is unique and should be individually managed, taking into consideration the physical-chemical properties of the drug as well as maternal-fetal exposure characteristics.
The knowledge obtained during the last decades about potential adverse effects of drug exposure during pregnancy have resulted in an increased concern about the best drug choice. So, FDA (Food and Drug Administration) has proposed a classification for drugs used and available in the market. Five different categories were suggested according to the risk of affecting embryo-fetal development 11:
Category A - Controlled studies showed absence of risk. Adequate and well controlled studies with pregnant women have shown no fetal risk.
Category B - Without evidences of human risk. Animal studies have not proven risk, but in humans either there are no adequate studies or animal studies are negative.
Category C - The risk cannot be ruled out. There is a lack of human studies and animal studies either are positive or are also lacking. Potential benefits, however, may justify a potential risk.
Category D - Positive evidence of risk. Preliminary or post-commercialization investigation data have shown fetal risk. Potential benefits, however, may override potential risk.
Category X - Contraindicated in pregnancy. Animal or human studies, preliminary or post-commercialization reports have shown fetal risk which clearly overrides any potential benefit for the patient.
According to this classification, drugs more frequently used in anesthesia are listed in Chart I 12,13.
ANESTHETIC DRUGS AND FETAL EFFECTS
Anesthesia in pregnant patients involves several situations which should be thoroughly analyzed. In addition to fetal exposure to anesthesia and to a potential toxic action of drugs, gestational age, drugs and doses should be taken into consideration.
One aspect to be considered is the possible interference of the anesthetic technique or of the drug action in the maternal-placental-fetal unit balance. When potential problems of obstetric anesthesia are analyzed, one concern is the non involvement of uterine contractility because a prolonged labor may result in fetal risk. In addition, drugs should not induce fetal depression.
In anesthesia for surgery during pregnancy, the concern with the maternal-fetal binomial is especially directed to preventing abortion or premature labor and uterine contractility decrease may be even useful. Fetal central nervous system depression is not a severe problem because drugs tend to return to the maternal body to be excreted 14.
An important aspect to be considered in anesthetic-surgical procedures during pregnancy is the possibility of normal fetal development impairment 14. So, in addition to the possibility of embryo-fetotoxic effect of the drug, the risk of adverse fetal effects caused by hypoxia, either due to pulmonary ventilation defficiency or to placental and/or intervillous blood flow interference, must be considered. Such blood flows may be impaired by systemic hypotension (as a consequence of general or regional anesthesia or vena cava compression) or by vasoconstriction caused by sympathicomimetic agents. These agents, when used to correct hypotension, may lead to uterine vasoconstriction thus impairing uterine perfusion 15. In this case, the best option would be ephedrine which, due to a hormonal mechanism does not significantly act upon pregnant uterus vessels 16. When ephedrine is contraindicated (tachycardia, cardiac valve stenosis, b-adrenergic agonists therapy) low doses of phenylephrine have shown to be satisfactory and may constitute a second choice 17.
Still related to the intervillous flow, a trend to placental vasoconstriction decreasing fetal pH can be observed whenever there is maternal alkalosis, either metabolic or respiratory 18.
Most anesthetic drugs easily cross the placenta through simple diffusion, but it must be reminded that during this process the balance between maternal and fetal compartments is achieved only by the free liposoluble fraction. Lidocaine (pKa of 7.8 to 36 ºC), routinely used in anesthesia, is a good example of what may occur. Supposing a stable maternal pH of 7.45 and a fetal pH varying from 7.35 to 7.20, the following calculation may be done: with a pH of 7.35, when a balance is achieved between both compartments, there will be, for each 100 non-ionized molecules at each side of the membrane, 224 ionized molecules at maternal and 282 at the fetal side by volume unit. If, however, fetal pH decreases to 7.20, there will be, for the same 224 maternal ionized molecules, 398 fetal molecules 9. So, fetal pH decrease leads to an absolute increase of approximately 30% of local anesthetic molecules in the fetus. If the child is born in this condition of low pH, as its acidosis is corrected, there is an increase in non-ionized anesthetic molecules which could induce toxicity. According to Tucker 19, it is usual to say that bupivacaine is safer than lidocaine because fetal-maternal concentrations ratio is 0.2 for bupivacaine and 0.5 for lidocaine. The fact is that the lack of acid glucoprotein a1 leads to a decrease in fetal local anesthetic binding. If analyzing the non-ionized fraction alone, maternal-fetal ratios will always be close to 1. The important is the ratio between drug toxic concentration and fetal blood concentration of free drug, which may be significantly higher for bupivacaine and etidocaine than for lidocaine and mepivacaine, thus indicating higher safety margins for the first two anesthetics.
Neuromuscular blockers are an important exception regarding transplacental crossing because they have quite high molecular weights and present in their structure two amino quaternary clusters meaning a high ionization level. These two characteristics, important to prevent their penetration in the central nervous system, minimize transplacental crossing of neuromuscular blockers 20.
The most popular anesthetic option for pregnant patients, especially for delivery - be it vaginal or cesarean section - is regional anesthesia. Here, local anesthetics cross the placenta very easily, but when maximum recommended doses are respected, there is a good maternal and fetal tolerance.
Some local anesthetic drugs, however, have peculiarities that should be considered. Prilocaine induces metahemo- globinemia more easily in fetus and newborn than in adults 4,21. As bupivacaine binds to red blood cells, decreasing their survival, it tends to worsen neonatal jaundice 22. Mepivacaine which, as all local anesthetics, tends to accumulate in the fetus due to maternal-fetal pH differences, is porly metabolized by the newborn liver and is found in the blood several days after its administration 23. Fetal liver immaturity affects in a higher or lesser degree, the metabolism of all amides. So, esters, such as chlorprocaine have been proposed for perineal infiltration because it is rapidly hydrolized by maternal esterases, so that practically only its inactive metabolite, chloroaminobenzoic acid, is found in maternal blood and, therefore, also in fetal blood 24.
As to general anesthesia, results are similar to regional anesthesia in normal maternal and fetal conditions. However, if there are fetal problems, the benefit of regional anesthesia may be significant 25. After general anesthesia, Apgar scores are usually worse at birth, but in the absence of hypoxia, hypotension, aorta and/or vena cava compression and excessive hyperventilation, the acid-base balance is not changed and the neonate has a satisfactory recovery 2,26. Neuro-behavioral indices may be affected, but for a short period. Time elapsed between induction of general anesthesia and fetal extraction is usually very valued. If this time is not longer than 8 to 10 minutes, newborn is in good condition because there is no time enough for factors such as maternal hyperventilation to induce fetal acidosis. In addition, if nitrous oxide is being used, a longer time will allow the installation of diffusion hypoxia 26,27. However, a factor which seems to be more important is the time elapsed between uterine incision and fetal extraction, which should not exceed 3 minutes, even in case of blockade 26.
Venous anesthetics in pregnant patients should be carefully evaluated due to problems they may trigger.
Propofol is rapidly uptaken and distributed through the tissues, leading to a fast maternal-fetal balance 28 with a fast decrease in fetal blood after birth. If used in continuous infusion, it seems to suffer metabolism or continuous uptake by fetal tissues 29 and this does not seem to be a good obstetric anesthesia technique although neonate neurological and adaptative indices are not significantly decreased 30. As compared to thiopental, such drug has contradictory results in neonate recovery scores 31-33. It has the advantage of decreasing hypertensive response to tracheal intubation 30,32, but it has already been shown that it relaxed isolated uterine muscles 34. In general, it does not seem to be advantageous as a routine for cesarean sections 2.
Thiopental also crosses the placental membrane, reaches umbilical vein concentration peak in less than two minutes and umbilical artery concentration peak in three to four minutes, after which maternal and fetal concentration starts to decrease 35. A large part of what goes to the fetus is metabolized by liver first passage and high thiopental concentrations have been found in fetal livers. This high concentration is caused by intense drug uptake by hepatocyte citoplasmatic proteins, which are also responsible for halothane and lidocaine uptake 36. Thiopental will only depress the fetus if used in excess of 8 mg.kg-1 37.
As to benzodiazepinics, midazolam although with a shorter half-life as compared to thiopental 38 and better maternal results (more circulatory stability, better hypnosis), causes more fetal depression especially during the first two hours of life 39,40. Neonatal neuro-behavioral tests, however, performed few hours after birth, have not shown significant differences as compared to thiopental 39. Diazepam, when used, is found in higher fetal than maternal concentrations 41, sometimes reaching a 2-1 ratio. Diazepam protein binding is decreased in pregnant women 42, allowing, after birth, the decrease of this binding in the neonate to result in depression.
Ketamine in cesarean section anesthesia may result in hypertension and tachycardia, making it inadequate for pre-eclampsia or eclampsia patients 2. The drug may be a good agent for anesthesia induction, especially in hypovolemic patients and does not affect the fetus if doses does not exceed 1.5 mg.kg-1 43,44.
Important progresses were achieved in this area of knowledge, but there are still many issues about the use of drugs during gestation. Anesthesiologists, however, have now new drugs and information to offer a good safety level to mother and fetus.
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to Submitted for publication May 28, 2001 *
Received from Universidade Católica de Pelotas, RS
Dr. Márcio Leal Horta
Rua Anchieta, 4043
96015-420 Pelotas, RS
Accepted for publication July 26, 2001
Submitted for publication May 28, 2001
* Received from Universidade Católica de Pelotas, RS