Abstract
Minor traumatic injuries are common in pregnancy, often subsequently requiring painful diagnostic and therapeutic procedures. Pregnant women who are experiencing significant pain, distress, or fear may benefit from procedural sedation in the emergency department. In this review we examine the fetal safety of specific drugs used for procedural sedation.
Résumé
Les lésions traumatiques mineures sont courantes au cours de la grossesse et elles nécessitent souvent, par la suite, la mise en œuvre d’interventions diagnostiques et thérapeutiques douloureuses. Les femmes enceintes qui connaissent de la douleur, de la détresse ou une peur considérable pourrait tirer avantage d’une sédation procédurale mise en œuvre au sein du service des urgences. Dans le cadre de cette analyse, nous examinons l’innocuité fœtale de certains des médicaments utilisés aux fins de la sédation procédurale.
Key Words
BACKGROUND
Between 6% and 7% of all pregnant women may be affected by some sort of traumatic injury,
1.
,2.
the most common of which are minor injuries such as fractures, sprains, or open wounds.3.
Treatment of these painful conditions may necessitate either local anaesthesia or procedural sedation. Other common procedures performed during pregnancy, such as dental procedures4.
and gastrointestinal endoscopic procedures5.
may also require sedation.Definitions
Procedural sedation and analgesia, previously (and inappropriately) termed “conscious sedation,” involves the use of short-acting analgesics and sedative medications to enable clinicians to perform procedures effectively while monitoring the patient closely for potential adverse effects.
6.
,7.
Common terms include the following:
Analgesia: relief of pain without intentionally producing a sedated state. Altered mental status may occur as a secondary effect of medications administered for analgesia.
Minimal sedation: the patient responds normally to verbal commands. Cognitive function and coordination may be impaired, but ventilatory and cardiovascular functions are unaffected.
Moderate sedation and analgesia: the patient responds purposefully to verbal commands alone or when accompanied by light touch. Protective airway reflexes and adequate ventilation are maintained without intervention. Cardiovascular function remains stable.
Deep sedation and analgesia: the patient cannot easily be roused, but responds purposefully to noxious stimulation. Assistance may be needed to ensure the airway is protected and adequate ventilation maintained. Cardiovascular function is usually stable.
General anaesthesia: the patient cannot be roused and often requires assistance to protect the airway and maintain ventilation. Cardiovascular function may be impaired.
Dissociative sedation: a trance-like cataleptic state in which the patient experiences profound analgesia and amnesia, but retains airway protective reflexes, spontaneous respirations, and cardiopulmonary stability. Ketamine is the pharmacologic agent used for procedural sedation that produces this state.
The risks in procedural sedation mainly include reaching a depth of sedation that is different from the planned level, respiratory depression or apnea, cardiovascular depression, and pulmonary aspiration of gastric contents.
8.
, 9.
, 10.
PHYSIOLOGIC CONSIDERATIONS
There are several key points to consider when sedating a pregnant woman.
11.
In pregnancy, there is an increase in maternal oxygen consumption and a decrease in functional residual capacity, both of which can contribute to the rapid decrease in maternal PaO2 that is observed even during brief apnea.
12.
In addition, there is mild maternal hyperventilation and decreased maternal PaCO2, an effect that is counteracted during procedural sedation and/or general anaesthesia.13.
, 14.
15.
Moreover, there is an increase in the risk of difficult intubation in pregnant women because of physiologic changes in the maternal airway during pregnancy,13.
,14.
and loss of airway control is the most common cause of anaesthesia-related maternal mortality.15.
Hemodynamic changes during pregnancy include a decrease in systemic blood pressure arising from progesterone-induced vasodilatation and the low-resistance placenta,
16.
systemic hypotension (especially in the supine position) due to aortocaval compression by the gravid uterus,17.
,18.
a significant increase in cardiac output, and a decrease in maternal hematocrit.19.
Pregnant women have an increased incidence of reflux esophagitis and heartburn, and this alone puts the pregnant patient at increased risk for gastric acid aspiration when sedated or anaesthetized after approximately 16 weeks’ gestation.
20.
Delayed gastric emptying, which was once thought to be a feature of all trimesters of pregnancy,21.
,22.
is now known to occur only during active labour and postpartum.23.
,24.
FETAL ASPHYXIA
Short periods of mild maternal hypoxemia may be well-tolerated by the fetus because of the high affinity of fetal hemoglobin for oxygen.
25.
However, maternal hypoxemia has been shown to be teratogenic in animals and humans and may result in fetal death.26.
,27.
Maternal hypercapnia (or hypocapnia), another possible risk of procedural sedation, may cause fetal respiratory acidosis, myocardial depression, and uterine artery vasoconstriction with subsequent reduced uterine blood flow.28.
Hypercapnia, with or without hypoxia, has been also found to be associated with an increased rate of cardiac malformations in rats.29.
,30.
Studies in vitro and in animals have inconsistently shown different adverse effects of increased oxygen concentration or hyperbaric oxygen on the developing fetus, but there is no human evidence of adverse fetal effects of short-term 100% oxygen administration to pregnant patients. Therefore, the general recommendation is to administer procedural sedation in conjunction with 100% oxygen delivered by mask.31.
, 32.
33.
, 34.
, 35.
, 36.
Maintaining normal maternal systemic blood pressure is another important aspect of procedural sedation because of the relative passive dependence of the uteroplacental circulation and the risk for fetal ischemia.11.
,35.
This necessitates close monitoring of maternal blood pressure, and hypotension can be prevented or treated by administering fluids or vasopressors.SPECIFIC DRUGS
The drugs most commonly used in procedural anaesthesia are midazolam, remifentanil, propofol, ketamine, and nitrous oxide.
Midazolam
Midazolam, a benzodiazepine, is used for anxiolysis and sedation. Human data regarding the teratogenicity of benzodiazepines are conflicting. A meta-analysis conducted by Motherisk in 1998 on the use of benzodiazepines in the first trimester of pregnancy
36.
showed a significant increase in risk of oral cleft (OR 1.79; 95% CI 1.13 to 2.82), but the reliability of these marginally significant results was low because of the heterogeneity of the case–control studies upon which they were based. In the same meta-analysis, pooled data from cohort studies showed no significant increase in major malformations (OR 0.9; 95% CI 0.61 to 1.35) or oral cleft (OR 1.19; 95% CI 0.34 to 4.15). In a study following 460 pregnancies exposed to benzodiazepines (98% in the first trimester) there was no significantly increased rate of malformations in the exposed group (3.1%) compared with control subjects (2.6%) (OR 1.2; 95% CI 0.5 to 2.8, P = 0.51).37.
In a 2007 study of benzodiazepine exposure from the Swedish Medical Birth Register that included 1979 infants, the rate of congenital malformations (5.3%) was comparable with that of all births in the registry (4.7%) (n = 873 879). The use of benzodiazepines near term was shown to be related to the “floppy infant syndrome,” especially in higher doses.38.
Remifentanil
Remifentanil is a rapid-onset, ultra-short-acting, synthetic µ-receptor agonist analgesic that is administered intravenously, either alone or in combination with other sedative drugs. There are several indications for this drug, including procedural sedation, labour analgesia, and induction of general anaesthesia.
7.
,39.
Remifentanil readily crosses the placenta, but evidence shows that it is rapidly metabolized and redistributed in the fetus.40.
There are no human data regarding the use of remifentanil in early pregnancy. However, opioid analgesics are not considered to be human teratogens.Propofol
Propofol is commonly used as an intravenous anaesthetic agent. It is short acting and rapidly cleared from the circulation,
41.
and therefore it is the anaesthetic of choice for short-duration surgical procedures.42.
In animal studies, propofol was not shown to be teratogenic.43.
Although maternal hypotension is a common adverse effect of propofol, one study showed that propofol has a dilating effect on fetal placental blood vessels, and therefore maintains appropriate umbilical blood flow.44.
Concerns have been raised about neonatal sedation and depression,45.
but several studies have shown similar Apgar scores and neurological and adaptive capacity scores with use of low dose (2 mg/kg) propofol and with spinal anaesthesia or barbiturates.46.
, 47.
, 48.
In one study, use of intravenous propofol was shown to decrease the one-minute Apgar score but not the five-minute score.49.
High-dose propofol (9 mg/kg) given peripartum may transiently depress neonatal neurobehavioural function.50.
In summary, there is no animal or human evidence for teratogenicity of propofol; however, there are concerns about neonatal depression when it is used close to delivery, especially in high doses.Ketamine
Ketamine is a rapid and short-acting general anaesthetic, producing an anaesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. In animal studies, high doses of ketamine were not shown to be teratogenic
51.
; however, two recent animal studies showed that exposure to high doses of ketamine (10 mg/kg, or more)for several hours may be associated with neuroapoptosis in the fetal brain in monkeys.52.
,53.
No human data regarding the teratogenicity of ketamine exist. Some studies demonstrated dose-dependent uterine contractions in early and late pregnancy,54.
, 55.
, 56.
but others did not.57.
,58.
These effects were more prominent in early pregnancy and with a maternal dose of 2 mg/kg or more. Ketamine is known to increase maternal blood pressure and heart rate by up to 30% to 40%, and it is therefore not recommended for use in women with pre-existing hypertension.59.
, 60.
, 61.
Neonatal depression is also a concern when ketamine is given close to delivery. Several studies have shown a dose-related significant decrease in one-minute and five-minute Apgar scores and in neurobehavioural status before 24 hours of age,
62.
, 63.
64.
, 65.
66.
while others have shown excellent Apgar scores.62.
In summary, the limited available human data suggests that ketamine may be used in low doses throughout pregnancy, but other agents may be preferable.Nitrous Oxide
Nitrous oxide (N2O), the most controversial inhalation anaesthetic in terms of safe use during pregnancy, is a non-flammable gas commonly used for analgesia and general anaesthesia. In several animal studies nitrous oxide was shown, in a dose-dependent manner, to increase rates of embryonic death, resorption, growth restriction, and malformations such as skeletal anomalies, fused ribs, limb defects, cleft palate, gut herniation, gastroschisis, encephalocele, hydrocephalus, anophthalmia, and gonadal agenesis.
63.
, 64.
, 65.
, 66.
, 67.
, 68.
, 69.
, 70.
, 71.
, 72.
Other studies have shown no significant reproductive effects.73.
, 74.
, 75.
Several epidemiologic studies have shown an association between spontaneous abortion and occupational exposure of women to nitrous oxide (among other substances) in operating rooms, dental clinics, and obstetric rooms76.
, 77.
, 78.
, 79.
; however, most of these studies were retrospective, did not specify the type of gases, did not demonstrate a dose–response relationship, and were conducted before anaesthetic gas scavenging had become a legal requirement.76.
Scavenging, and possibly vitamin B12supplements,80.
may minimize and possibly eliminate any risk. Several studies have failed to show an increased risk for congenital malformations in the offspring of mothers exposed to general anaesthesia, including nitrous oxide, in different trimesters of pregnancy.81.
, 82.
, 83.
, 84.
One population-based case–control study has shown an increased risk for central nervous system defects; however, specific anaesthetic agents were not identified.85.
N2O exposure was also found to be associated with lower birth weights and a higher incidence of babies small for gestational age in several retrospective studies.86.
, 87.
, 88.
, 89.
Several other concerns about nitrous oxide toxicity have been raised, including conflicting evidence regarding neurotoxicity and minor neurological impairments in the offspring,90.
,91.
neonatal acidosis and low Apgar scores in prolonged maternal N2O exposure,92.
and childhood leukemia.93.
In summary, short duration exposure to N2O may pose no significant risk for the fetus, but the availability of a wide range of safer anaesthetic alternatives may give N2O a lower priority among agents used for procedural anaesthesia in pregnant women.CONCLUSION
Emergency medical issues may arise throughout pregnancy, necessitating immediate, painful diagnostic and therapeutic interventions. Pregnant women who are in pain may suffer even more from the painful intervention and the secondary anxiety, necessitating procedural sedation. In most instances, the exposure to the medications used in procedural sedation is brief, and the doses are relatively low; therefore, significant adverse pregnancy outcomes are not expected. The current evidence suggests that pregnant women who need a surgical intervention and who have significant pain, distress, or fear may benefit from procedural sedation in the emergency department setting. This should be provided under the supervision of a physician with expertise in obstetric anaesthesia. More prospective studies are critical to further evaluate the safety of those specific medications in pregnancy.
REFERENCES
- Trauma and pregnancy.Am J Pennatol. 1997; 14: 331-336
- Trauma in pregnancy: maternal and fetal outcomes.J Trauma. 1998; 45: 83-86
- Trauma during pregnancy: an analysis of maternal and fetal outcomes in a large population.Am J Obstet Gynecol. 2004; 190: 1661-1668
- Dental care during pregnancy.Can Fam Physician. 2009; 55: 598-599
- Sedation and analgesia for gastrointestinal endoscopy during pregnancy.Gastrointest Endosc Clin N Am. 2006; 16: 1-31
- Pharmacokinetic and pharmacodynamic characteristics of medications used for moderate sedation.Clin Pharmacokinet. 2006; 45: 855-869
- Procedural sedation and analgesia in the emergency department: recommendations for physician credentialing, privileging, and practice.Ann Emerg Med. 2011; 58: 365-370
- Practice guidelines for sedation and analgesia by non-anesthesiologists.Anesthesiology. 2002; 96: 1004-1017
- Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department.Ann Emerg Med. 2003; 42: 636-646
- Fasting is a consideration—not a necessity—for emergency department procedural sedation and analgesia.Ann Emerg Med. 2003; 42: 647-650
- Anaesthetic considerations for non-obstetric surgery during pregnancy.Br J Anaesth. 2011; 107: i72-i78
- Respiratory physiology in pregnancy.Clin Chest Med. 2011; 32 (vii.): 1-13
- Relative risk analysis of factors associated with difficult intubation in obstetric anesthesia.Anesthesiology. 1992; 77: 67-73
- Failed tracheal intubation in obstetrics: no more frequent but still managed badly.Anaesthesia. 2005; 60: 168-171
- Anesthesia-related maternal mortality in the United States: 1979-2002.Obstet Gynecol. 2011; 117: 69-74
- Control mechanisms for physiological hypertrophy of pregnancy.Circulation. 1996; 94: 667-672
- Effects of the pregnant uterus on the extradural venous plexus in the supine and lateral positions, as determined by magnetic resonance imaging.Br J Anaesth. 1997; 78: 317-319
- Supine hypotensive syndrome.Obstet Gynecol. 1994; 83: 774-788
- Cardiac surgery during pregnancy.J. Heart Valve Dis. 2006; 15: 686-690
- Anesthesia for nonobstetric surgery in the pregnant patient.Semin Perinatol. 2002; 26: 136-145
- Gastric emptying is delayed at 8-12 weeks’ gestation.Br J Anaesth. 1994; 73: 237-238
- Pregnancy delays paracetamol absorption and gastric emptying in patients undergoing surgery.Br J Anaesth. 1988; 60: 2-7
- Gastric emptying in pregnancy.Br J Anaesth. 1991; 67: 54-57
- An evaluation of gastric emptying times in pregnancy and the puerperium.Anaesthesia. 1993; 48: 53-57
- The effect of reducing umbilical blood flow on fetal oxygenation.Am J Obstet Gynecol. 1983; 145: 813-818
- Effects of prenatal hypoxia on the cardiovascular system in the rat.Arch Pathol. 1965; 80: 351-356
- Uterine and systemic hemodynamic interrelationships and their response to hypoxia.Am J Obstet Gynecol. 1969; 103: 138-157
- Effects of hypercapnia on uterine and umbilical circulations in conscious pregnant sheep.J Appl Physiol. 1976; 41: 727-733
- Cardiac malformations in rats induced by exposure of the mother to carbon dioxide during pregnancy.Circ Res. 1960; 8: 1218-1227
- Cardiac malformations in the rat induced by maternal hypercapnia with hypoxia.Circ Res. 1966; 19: 544-551
- Effects of different oxygen concentrations on the development of rat embryos in culture.J Reprod Fertil. 1970; 21: 109-118
- Effects of oxygen toxicity on early development of mouse embryos.Mol Reprod Dev. 1992; 31: 28-33
- Oxygen-induced embryopathy and the significance of glutathione-dependent antioxidant system in the rat embryo during early organogenesis.Free Radic Biol Med. 1997; 22: 447-454
- Anesthesia for nonobstetric surgery during pregnancy.Mt Sinai J Med. 1998; 65: 265-270
- Review: the angiogenic and vasodilatory uteroplacental network.Placenta. 2011; 32: S170-S175
- Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies.BMJ. 1998; 317: 839-843
- Is benzodiazepine use during pregnancy really teratogenic?.Reprod Toxicol. 1998; 12: 511-515
- The effects of benzodiazepine use during pregnancy and lactation.Reprod Toxicol. 1994; 8: 461-475
- Systemic remifentanil for labor analgesia.Anesth Analg. 2009; 109: 1925-1929
- Intravenous remifentanil: placental transfer, maternal and neonatal effects.Anesthesiology. 1998; 88: 1467-1564
- Propofol: a new intravenous anesthetic.Anesthesiology. 1989; 71: 260-277
- Predicted propofol effect-site concentration for induction and emergence of anesthesia during early pregnancy.Anesth Analg. 2009; 109: 90-95
- Effects of propofol and thiopental on maternal and fetal cardiovascular and acid-base variables in the pregnant ewe.Anesthesiology. 1993; 78: 562-576
- Effect of propofol on human fetal placental circulation.Int J Obstet Anesth. 2010; 19: 71-76
- Neurobehavioural effects of propofol on the neonate following elective caesarean section.Br J Anaesth. 1989; 62: 649-654
- Intravenous infusion of low dose propofol for conscious sedation in cesarean section before spinal anesthesia.Acta Anaesthesiol Sin. 1997; 35: 79-84
- Plasma catecholamines and neonatal condition after induction of anaesthesia with propofol or thiopentone at caesarean section.Br J Anaesth. 1993; 70: 311-316
- Intravenous propofol vs thiamylal-isoflurane for caesarean section, comparative maternal and neonatal effects.Acta Anaesthesiol Scand. 1995; 39: 205-209
- Propofol and thiopentone for caesarean section revisited: maternal effects and neonatal outcome.Int J Obstet Anesth. 1991; 1: 19-23
- Propofol for induction and maintenance of anaesthesia at caesarean section. A comparison with thiopentone/enflurane.Anaesthesia. 1991; 46: 20-23
- Parke-Davis product information.Ketalar. 1993;
- Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain.Anesthesiology. 2012; 116: 372-384
- Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys.Neurotoxicol Teratol. 2011; 33: 220-230
- Effects of ketamine on the pregnant uterus.Br J Anaesth. 1979; 51: 1163-1166
- Ketamine for obstetric delivery.Anesthesiology. 1976; 44: 522-524
- Ketamine and the pregnant uterus.Can Anaesth Soc J. 1973; 20: 141-145
- Ketamine in obstetric anesthesia: special reference to placental transfer and its concentration in blood plasma.Acta Obstet Gynaecol Jpn. 1972; 19: 80-93
- Induction agents for Caesarean section. A comparison of thiopentone and ketamine.Anaesthesia. 1973; 28: 37-42
- Study of ketamine as an obstetric anesthetic agent.Am J Obstet Gynecol. 1972; 113: 247-260
- Current status of ketamine anaesthesia.Lancet. 1971; 1: 1285-1288
- Ketamine and diazepam as anaesthesia for forceps delivery. A comparative study.Acta Anaesthesiol Scand. 1977; 21: 37-40
- Ketamine as induction agent for caesarean section.Acta Anaesthesiol Scand. 1982; 26: 139-142
- Teratogenic activity of nitrous oxide.Nature. 1967; 214: 146-148
- Effects of low concentrations of nitrous oxide on rat pregnancy.Anesthesiology. 1973; 39: 299-301
- Fetotoxicity in rats following chronic exposure to halothane, nitrous oxide, or methoxyflurane.Anesthesiology. 1978; 48: 11-16
- Effects of nitrous oxide during organogenesis in the rat.J Dent Res. 1979; 58: 1940-1943
- Effects of low concentrations of nitrous oxide on rat fetuses.Anesth Analg. 1980; 59: 175-177
- Effects of low intermittent concentrations of nitrous oxide on the developing rat fetus.Br J Anaesth. 1983; 55: 67-69
- The effects of nitrous oxide on the developing hamster embryos.Can J Physiol Pharmacol. 1979; 57: 1229-1232
- Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not.Science. 1980; 210: 899-901
- Reproduction and fetal development in rats exposed to nitrous oxide.Teratology. 1984; 30: 259-265
- Susceptible period of nitrous oxide teratogenicity in Sprague-Dawley rats.Teratology. 1989; 40: 439-444
- Chronic exposure to low concentrations of halothane-nitrous oxide: reproductive and cytogenetic effects in the rat.Anesthesiology. 1979; 50: 310-318
- Toxicity of low concentration long-term exposure to an airborne mixture of nitrous oxide and halothane.J Environ Pathol Toxicol. 1979; 2: 209-231
- Reproduction and fetal development in mice chronically exposed to nitrous oxide.Teratology. 1982; 26: 11-16
- Occupational exposure to inhaled anesthetic. Is it a concern for pregnant women?.Can Fam Physician. 2000; 46: 2391-2392
- Risk of spontaneous abortion in women occupationally exposed to anaesthetic gases: a meta-analysis.Occup Environ Med. 1997; 54: 541-548
- Reproductive outcomes among dental personnel: a review of selected exposures.J Can Dent Assoc. 2006; 72: 821-825
- Health experiences of operating room personnel.Anesthesiology. 1985; 62: 325-330
- Vitamin B12 supplements as protection against nitrous oxide inhalation.N Y State Dent J. 1994; 60: 47-49
- Pregnancy outcome following non-obstetric surgical intervention.Am J Surg. 2005; 190: 467-473
- Surgery during pregnancy and fetal outcome.Am J Obstet Gynecol. 1980; 138: 1165-1167
- Nitrous oxide in early human pregnancy.Anaesthesia. 1986; 41: 900-905
- Reproductive outcome after anesthesia and operation during pregnancy: a registry study of 5405 cases.Am J Obstet Gynecol. 1989; 161: 1178-1185
- Neural tube defects and first trimester operations.Teratology. 1990; 41: 717-720
- Anesthesia, pregnancy, and miscarriage: a study of operating room nurses and anesthetists.Anesthesiology. 1971; 35: 343-347
- Outcome of pregnancy among women in anaesthetic practice.Lancet. 1977; 1: 34-36
- Health problems of anaesthetists and their families in the West Midlands.Br Med J. 1979; 1: 779-784
- The association of shift work and nitrous oxide exposure in pregnancy with birth weight and gestational age.Epidemiology. 1999; 10: 429-436
- Developmental evaluation of children born to mothers occupationally exposed to waste anesthetic gases.Birth Defects Res Part A Clin Mol Teratol. 2004; 70: 476-482
- Neurologic activity of infants following anesthesia for cesarean section.Anesthesiology. 1978; 48: 350-356
- Neonatal effect of prolonged anesthetic induction for cesarean section.Obstet Gynecol. 1981; 58: 331-335
- Maternal and perinatal risk factors for childhood leukemia.Cancer Res. 1991; 51: 3696-3701
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Footnotes
Competing Interests: None declared.
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© 2013 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.
