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Anesthesia, Cardiopulmonary Bypass, and the Pregnant Patient

      For the perioperative management of pregnant patients with severe cardiac or aortic disease who require a cardiac surgical procedure and cardiopulmonary bypass, a close, cohesive, working relationship must exist among several medical and surgical specialties. For appropriate management, the well-being of both the mother and the fetus must be considered. The best interests of the mother and the fetus may not coincide, and optimal therapy for one may be inappropriate for the other. We present 10 cases of severe cardiac or aortic disease in pregnant women who required surgical intervention. Eight patients underwent cardiopulmonary bypass during pregnancy, and two patients had cesarean section performed immediately before cardiopulmonary bypass. We also discuss the pertinent pharmacologic aspects related to the perioperative period and the management of cardiopulmonary bypass for the pregnant patient.
      Cardiac disease occurs in fewer than 2% of pregnant women;
      • Otterson WN
      • Dunnihoo DR
      Cardiac disease.
      therefore, most clinicians are rarely concerned with this problem. The care of the pregnant patient with heart disease can be challenging, inasmuch as two lives are involved. The patient with cardiovascular disease who is well compensated in the nonpregnant state may have acute cardiac decompensation as the demand on the cardiorespiratory system increases substantially during pregnancy. During labor and delivery, the cardiac output may be twice that of the nonpregnant state, and a patient who has severe cardiac impairment, whether it is the result of congenital, rheumatic, or coronary artery disease, may have an increased risk for decompensation.
      Fetal mortality may exceed 50% in women with severe, untreated congenital heart disease.
      • McAnulty JH
      • Metcalfe J
      • Ueland K
      Heart disease and pregnancy.
      Although studies of outcome have suggested no increase in maternal mortality associated with cardiopulmonary bypass (CPB), the related fetal mortality is high.
      • Bernal JM
      • Miralles PJ
      Cardiac surgery with cardiopulmonary bypass during pregnancy.
      Even though profound hypothermic bypass may be correct for the nonpregnant patient, it can be hazardous for the fetus. Nonpulsatile blood flow and hypotension associated with CPB may adversely affect placental blood flow. Recent reviews of cardiac disease during pregnancy
      • Otterson WN
      • Dunnihoo DR
      Cardiac disease.
      • McAnulty JH
      • Metcalfe J
      • Ueland K
      Heart disease and pregnancy.
      have not dealt in depth with the dramatic maternal and fetal physiologic alterations that occur during CPB and general anesthesia. In this report, we present eight cases at our institution of CPB during pregnancy for the correction or palliation of life-threatening cardiac or aortic lesions. For comparison, we also present two cases in which cesarean section was performed before the initiation of CPB. Pertinent aspects about the physiologic features of pregnancy, perioperative pharmacologic therapy, and CPB will be discussed.

      DISCUSSION OF 10 CASES

      The Mayo Clinic experience with pregnant patients who required cardiac or aortic surgical procedures is summarized in Table 1. Maternal age ranged from 17 to 43 years, and gestational age varied from 7 to 35 weeks.
      Table 1Summary of 10 Mayo Clinic Cases of Cardiac or Aortic Surgical Procedures in Pregnant Patients (1965 Through 1989)
      The fetal heart tones were monitored in three patients (cases 8, 9, and 10), and fetal distress as indicated by fetal bradycardia was detected in two (preoperatively in case 8 and during induction of anesthesia in case 10, which prompted performance of a cesarean). CPB = cardiopulmonary bypass; CPR = cardiopulmonary resuscitation; EGA = estimated gestational age; hypn = hypertension; L = left; mod = moderate; neuro = neurologic; PA = pulmonary artery; R = right; RDS = respiratory distress syndrome; RV = right ventricular; SV = supraventricular; temp = temperature; TI = tricuspid insufficiency; VSD = ventricular septal defect; WPW = Wolff-Parkinson-White.
      CaseAge (yr)Gestation (wk)
      At time of operation.
      DiagnosisIndication for operationSurgical procedureCPB time (min)
      CPB flows ranged from 2.0 to 2.4 liters/min per m2.
      Lowest tempType of deliveryEGAOutcome
      1288Tetralogy of Fallot, Pott's shuntCardiac failureTetralogy repair10124°C
      This patient had circulatory arrest for 16 minutes.
      Cesarean35 wkNormal baby
      24314Calcific aortic stenosisCardiac failureAortic valve replacement6436°CCesareanTermNormal baby
      32117Severe aortic stenosis, mitral regurgitation and stenosisSyncope and paroxysmal SV tachycardiaAortic and mitral valve replacements7332°CVaginalTermStillborn
      41720Aneurysm of descending thoracic aortaExpanding aneurysmResection of aneurysm, insertion of graft3935°CVaginalTermSmall baby with VSD
      5187Ebstein's anomaly, WPW syndromeRefractory arrhythmias, TIAccessory pathway ablation, tricuspid annuloplasty10223°CCesarean32 wkNormal baby
      62215Mitral regurgitation, cleft mitral valvePulmonary edemaMitral valve repair4732°CCesarean36 wkMultiple congenital defects
      72735Thrombosed mechanical aortic valveSevere cardiac failure, pulmonary edemaDébridement of aortic valve15428°CElective cesarean before CPB35 wkMaternal death
      82425Severe mitral stenosis, mod tricuspid regurgitation, increased RV and PA pressures, severe pregnancy-induced hypnSevere mitral stenosisMitral valve replacement5328°CFetus died intraoperatively25 wkApgar scores of 0 and 4, CPR needed, RDS, developmental delay
      93525Patent foramen ovaleNeuro deficit after R-L embolusClosure of patent foramen1836°CVaginal38 wkNormal baby
      103030Biscuspid aortic valve, severe stenosisSevere aortic stenosis, cardiac failureAortic valve replacement12820°CEmergency cesarean before CPB30 wkPrematurity and RDS
      * The fetal heart tones were monitored in three patients (cases 8, 9, and 10), and fetal distress as indicated by fetal bradycardia was detected in two (preoperatively in case 8 and during induction of anesthesia in case 10, which prompted performance of a cesarean). CPB = cardiopulmonary bypass; CPR = cardiopulmonary resuscitation; EGA = estimated gestational age; hypn = hypertension; L = left; mod = moderate; neuro = neurologic; PA = pulmonary artery; R = right; RDS = respiratory distress syndrome; RV = right ventricular; SV = supraventricular; temp = temperature; TI = tricuspid insufficiency; VSD = ventricular septal defect; WPW = Wolff-Parkinson-White.
      At time of operation.
      CPB flows ranged from 2.0 to 2.4 liters/min per m2.
      § This patient had circulatory arrest for 16 minutes.
      Six patients had severe aortic or mitral valve disease (or both), and one patient each had tetralogy of Fallot, an aneurysm of the descending thoracic aorta, Wolff-Parkinson-White syndrome and Ebstein's anomaly, and a patent foramen ovale. Indications for surgical treatment were related to cardiac complications associated with the increased demands that pregnancy placed on the heart, an expanding aortic aneurysm, intractable arrhythmias, and the need to prevent further central nervous system embolic injury from right-to-left shunting associated with a patent foramen ovale. Two patients (cases 7 and 10) underwent cesarean section before CPB.
      The total CPB time for the pregnant patients ranged from 18 to 102 minutes. Of considerable interest, one patient (case 1) had circulatory arrest for 16 minutes at a core temperature of 24°C. Another patient (case 5) denied the possibility of being pregnant and was cooled to 23°C, without circulatory arrest. In the other pregnant patients on CPB, the temperature ranged from 28°C to 36°C. Various primary anesthetic techniques were used: a combination of isoflurane and fentanyl citrate in four cases (cases 6, 8, 9, and 10), halothane alone in three (cases 1, 2, and 4) and with meperidine hydrochloride in one (case 5), ketamine hydrochloride and fentanyl citrate in one (case 7), and meperidine hydrochloride and nitrous oxide in one (case 3). In addition, three patients (cases 7, 8, and 10) had post-CPB inotropic or vasodilator therapy.
      Postoperative premature labor developed in only one patient (case 9) and resolved after intravenous administration of magnesium sulfate. One fetus, at 25 weeks of gestation, died intraoperatively. Three fetuses were delivered 4 to 8 weeks preterm after premature labor. One baby delivered at term was stillborn, and another had multiple congenital abnormalities.
      It is important to emphasize the management dilemma involved with these types of patients. Sometimes determining the best therapeutic choice and deciding whether the mother or the fetus should receive priority are difficult challenges. In one patient (case 7) in the 35th week of gestation, the baby was delivered by cesarean section before the cardiac procedure. After delivery of the baby, the mother sustained a cardiac arrest, and CPB was instituted emergently. After the initial attempt to discontinue CPB, the hemodynamics deteriorated after administration of protamine sulfate, and CPB had to be resumed. Subsequently, the patient could not be weaned from CPB. Another patient (case 10), who had severe aortic stenosis and acute cardiac decompensation at 30 weeks of gestation, was to undergo aortic valve replacement in an effort to allow the baby a few more weeks to mature. During the induction of anesthesia, fetal bradycardia suggestive of fetal distress occurred. The baby was delivered by cesarean section, and the mother tolerated the delivery and subsequent cardiac operation without major problems.

      PHYSIOLOGIC CHANGES OF PREGNANCY

      Physiologic changes that occur during pregnancy frequently alter the management of anesthesia and cardiac surgical procedures. The adverse consequences of these changes can usually be minimized if they are understood and appreciated. We will review the pertinent aspects of physiologic changes during pregnancy, and further details may be found in several recent publications.
      • Otterson WN
      • Dunnihoo DR
      Cardiac disease.
      • McAnulty JH
      • Metcalfe J
      • Ueland K
      Heart disease and pregnancy.
      • Cheek TG
      • Gutsche BB
      Maternal physiologic alterations during pregnancy.
      Uterine blood flow (UBF) is approximately 3% of the total cardiac output during the first trimester and increases to approximately 10 to 15% during the third trimester. This change, in addition to a decrease in systemic vascular resistance, results in an increased cardiac output that reaches a level approximately 30 to 40% above the nonpregnant level by the 30th week of gestation. The blood pressure (BP) normally remains unchanged or decreases slightly despite the increase in cardiac output.
      During the second and third trimesters, the enlarging uterus can mechanically produce compression of the inferior vena cava against the spine, especially when the pregnant patient is in the supine position. This situation will decrease venous return and cardiac output and may substantially diminish uteroplacental perfusion. Compression of the aorta by the gravid uterus can also decrease uteroplacental perfusion. Thus, after the first trimester, the supine position must be avoided intraoperatively if possible, either by placing a wedge or blanket roll beneath the right hip or by rotating the operating table to the left. Such measures should displace the gravid uterus off the major abdominal vessels without appreciably altering the operative field.
      Mechanical ventilation can profoundly affect uterine blood and the fetus. In nonanesthetized pregnant ewes, mechanical hyperventilation resulted in a decrease in UBF of 25% during hypocarbia and, with the addition of carbon dioxide to the respiratory gases, during normocarbia and hypercarbia.
      • Levinson G
      • Shnider SM
      • deLorimier AA
      • Steffenson JL
      Effects of maternal hyperventilation on uterine blood flow and fetal oxygenation and acid-base status.
      Maternal BP remained unchanged during hyperventilation, and the adverse effect on UBF was thought to be the result of the mechanical effects of positive-pressure ventilation—that is, a decrease in venous return and cardiac output.
      • Levinson G
      • Shnider SM
      • deLorimier AA
      • Steffenson JL
      Effects of maternal hyperventilation on uterine blood flow and fetal oxygenation and acid-base status.
      In a similar study, UBF decreased with the production of respiratory alkalemia by hyperventilation in anesthetized pregnant ewes.
      • Motoyama EK
      • Rivard G
      • Acheson F
      • Cook CD
      The effect of changes in maternal pH and Pco2 on the Po2 of fetal lambs.
      Maternal hyperventilation and respiratory alkalemia also decrease fetal arterial oxygen tension and oxygen content despite increases in maternal oxygenation.
      • Levinson G
      • Shnider SM
      • deLorimier AA
      • Steffenson JL
      Effects of maternal hyperventilation on uterine blood flow and fetal oxygenation and acid-base status.
      • Motoyama EK
      • Rivard G
      • Acheson F
      • Cook CD
      The effect of changes in maternal pH and Pco2 on the Po2 of fetal lambs.
      Maternal metabolic alkalemia produced by the administration of sodium bicarbonate similarly results in a decreased fetal arterial oxygen tension and oxygen content.
      • Motoyama EK
      • Rivard G
      • Acheson F
      • Cook CD
      The effect of changes in maternal pH and Pco2 on the Po2 of fetal lambs.
      • Ralston DH
      • Shnider SM
      • deLorimier AA
      Uterine blood flow and fetal acid-base changes after bicarbonate administration to the pregnant ewe.
      This diminished fetal arterial oxygen tension is probably attributable to a left shift of the maternal oxygen-hemoglobin dissociation curve.

      FETAL MONITORING AND MANAGEMENT

      Because fetal mortality is increased in pregnant women who undergo a surgical procedure and CPB,
      • Bernal JM
      • Miralles PJ
      Cardiac surgery with cardiopulmonary bypass during pregnancy.
      an understanding of potential problems and how to treat them may improve fetal outcome. The baseline fetal heart rate (FHR) normally varies from 120 to 160 beats/min. It can be reliably monitored transabdominally by Doppler techniques as early as the 12th week of gestation. FHR, variability of FHR, and uterine activity may be useful in evaluating the fetal status during anesthesia and a surgical procedure.
      Intraoperative fetal tachycardia may occur because of placental transfer after maternal administration of drugs such as sympathomimetics (for example, ritodrine hydrochloride and terbutaline sulfate) or parasympatholytics (for example, atropine sulfate). Fetal bradycardia may be due to fetal hypoxia or acidosis, maternal hypothermia, or the placental transfer of maternally administered drugs such as propranolol hydrochloride. Fetal hypoxia that produces bradycardia may result from a decrease in the oxygen content of maternal blood, a decrease in uterine perfusion pressure, or an increase in uterine artery resistance. The last two factors decrease the delivery of oxygen to the placenta by decreasing UBF.
      Variability in FHR is considered a measure of fetal well-being. Maternal factors such as hypoxemia, fever, and the administration of various medications, including local and general anesthetics, benzodiazepines, narcotics, and atropine, decrease the variability of the FHR. Although general anesthesia reduces the variability, the FHR usually remains in the normal range. The variability of the FHR reverts to normal when use of anesthetics or other drugs is discontinued.
      • Liu PL
      • Warren TM
      • Ostheimer GW
      • Weiss JB
      • Liu LMP
      Foetal monitoring in parturients undergoing surgery unrelated to pregnancy.
      Fetal factors that reduce the variability include acidosis, immaturity, and sleep cycles. The effects of uterine contractions on FHR are beyond the scope of this article but can be reviewed in appropriate obstetric textbooks.
      Risks to the fetus and the potential for premature labor necessitating delivery need to be discussed preoperatively with the patient. Fetal morbidity and mortality are substantial if delivery occurs at 24 to 26 weeks of gestation, and long-term neurologic sequelae occur in at least 20% of these premature fetuses. After 26 weeks of gestation, most tertiary-care centers achieve 80% survival, and the outcome is good. Cesarean section during CPB has been reported,
      • Martin MC
      • Pernoll ML
      • Boruszak AN
      • Jones JW
      • LoCicero III, J
      Cesarean section while on cardiac bypass: report of a case.
      and emergency cesarean section should be seriously considered at this gestational age if severe fetal bradycardia occurs, even if the patient is on CPB. At 30 weeks of gestation, more than 99% of fetuses will survive if delivered, and prebypass cesarean section should be considered. Fetuses after 34 weeks of gestational age should be delivered before a maternal bypass procedure if the maternal status allows.
      Another perinatal consideration in mothers who require surgical treatment of congenital heart disease is the increased incidence of fetal congenital heart disease.
      • Otterson WN
      • Dunnihoo DR
      Cardiac disease.
      • Whittemore R
      • Hobbins JC
      • Engle MA
      Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease.
      At 16 weeks of gestation and later, fetal echocardiography can be performed, and those fetuses with severe cardiac lesions can be managed appropriately. Detailed high-resolution ultrasound examination of the fetus can also be performed to evaluate noncardiac anatomy; thus, appropriate decisions can be made if other severe fetal abnormalities are identified.

      PHARMACOLOGIC CONSIDERATIONS

      Reportedly, 0.4 to 2.2% of women undergo anesthesia and surgical treatment while pregnant.
      • Brodsky JB
      • Cohen EN
      • Brown Jr, BW
      • Wu ML
      • Whitcher C
      Surgery during pregnancy and fetal outcome.
      • Shnider SM
      • Webster GM
      Maternal and fetal hazards of surgery during pregnancy.
      • Smith BE
      Fetal prognosis after anesthesia during gestation.
      Concerns about fetal development and teratogenicity exist whenever any drug is administered to pregnant women, especially during the first trimester when fetal organogenesis is occurring. The effects of isolated exposures to various anesthetics in pregnant humans have not, for the most part, been elucidated. Randomized clinical trials to assess the effects of drugs on the pregnant human female, the uteroplacental unit, and the fetus are neither ethical nor feasible. Thus, the information published about the effects of anesthetics and other drugs used during cardiac operations has been obtained from human studies limited by these restrictions and from animal studies that frequently have not simulated clinical situations. As a result, many aspects about the effects of drugs on the maternofetal unit are uncertain or unknown. Drugs used for anesthesia do not seem to cause fetal abnormalities.
      • Brodsky JB
      • Cohen EN
      • Brown Jr, BW
      • Wu ML
      • Whitcher C
      Surgery during pregnancy and fetal outcome.
      • Shnider SM
      • Webster GM
      Maternal and fetal hazards of surgery during pregnancy.
      • Smith BE
      Fetal prognosis after anesthesia during gestation.
      • Duncan PG
      • Pope WDB
      • Cohen MM
      • Greer N
      Fetal risk of anesthesia and surgery during pregnancy.
      In one study, premature labor and delivery were found to occur primarily as a result of the disorder that necessitated the surgical procedure and not as a result of the anesthetic agent, and no specific anesthetic technique or agent was superior to others.
      • Shnider SM
      • Webster GM
      Maternal and fetal hazards of surgery during pregnancy.
      In another study, in which 2,565 pregnant women who required surgical treatment during the first and second trimesters were compared with the same number of matched control subjects,
      • Duncan PG
      • Pope WDB
      • Cohen MM
      • Greer N
      Fetal risk of anesthesia and surgery during pregnancy.
      operative intervention, especially gynecologic procedures performed under general anesthesia, resulted in an increased rate of abortion, although no increase was noted in congenital malformations. The authors were unable to determine whether the operation or the effects of anesthesia on the uterus and UBF caused the increased rate of abortions.

      DRUGS COMMONLY USED DURING CARDIAC OPERATIONS

      Induction Agents.

      The commonly used nonnarcotic induction agents include thiopental sodium, ketamine, etomidate, and benzodiazepines such as diazepam and midazolam hydrochloride. As familiarity with propofol increases, this agent may also assume a more prominent role for induction of anesthesia for cardiac surgical procedures.
      Thiopental administered to parturients at cesarean section has been shown to have a larger apparent and steady-state volume of distribution when compared with that in nonpregnant women, and the elimination half-life for thiopental is also longer.
      • Morgan DJ
      • Blackman GL
      • Paull JD
      • Wolf LJ
      Pharmacokinetics and plasma binding of thiopental. II. Studies at cesarean section.
      A rapid transfer of thiopental from the human maternal circulation into placental tissue and amniotic fluid occurs during the first trimester of pregnancy
      • Jørgensen NP
      • Walstad RA
      • Molne K
      The concentrations of ceftazidime and thiopental in maternal plasma, placental tissue and amniotic fluid in early pregnancy.
      and at term.
      • Bakke OM
      • Haram K
      • Lygre T
      • Wallem G
      Comparison of the placental transfer of thiopental and diazepam in caesarean section.
      In pregnant ewes, UBF has been shown to decrease 20% without a substantial decline in maternal BP after induction of anesthesia with thiopental and succinylcholine, intubation, and use of nitrous oxide in oxygen for maintenance anesthesia.
      • Palahniuk RJ
      • Cumming M
      Foetal deterioration following thiopentone-nitrous oxide anaesthesia in the pregnant ewe.
      In that study, fetal oxygen saturation and pH also declined concurrently. This adverse effect on the fetus may have been caused by a light depth of anesthesia, sympathetic stimulation, and uterine vasoconstriction. Cosmi and Shnider
      • Cosmi EV
      • Shnider SM
      Obstetric anesthesia and uterine blood flow.
      also reported that clinical doses of thiopental reduce maternal BP and UBF in pregnant ewes.
      Ketamine has also been extensively studied in pregnant ewes and does not seem to affect the fetus or UBF adversely.
      • Craft Jr, JB
      • Coaldrake LA
      • Yonekura ML
      • Dao SD
      • Co EG
      • Roizen MF
      • Mazel P
      • Gilman R
      • Shokes L
      • Trevor AJ
      Ketamine, catecholamines, and uterine tone in pregnant ewes.
      • Levinson G
      • Shnider SM
      • Gildea JE
      • deLorimier AA
      Maternal and foetal cardiovascular and acid-base changes during ketamine anaesthesia in pregnant ewes.
      • Swartz J
      • Cumming M
      • Biehl D
      The effect of ketamine anaesthesia on the acidotic fetal lamb.
      In pregnant ewes
      • Craft Jr, JB
      • Coaldrake LA
      • Yonekura ML
      • Dao SD
      • Co EG
      • Roizen MF
      • Mazel P
      • Gilman R
      • Shokes L
      • Trevor AJ
      Ketamine, catecholamines, and uterine tone in pregnant ewes.
      and humans,
      • Ellingson A
      • Haram K
      • Sagen N
      • Solheim E
      Transplacental passage of ketamine after intravenous administration.
      placental transfer from mother to fetus is rapid. Appreciable adverse effects on UBF in pregnant ewes did not occur with 0.7 mg/kg
      • Craft Jr, JB
      • Coaldrake LA
      • Yonekura ML
      • Dao SD
      • Co EG
      • Roizen MF
      • Mazel P
      • Gilman R
      • Shokes L
      • Trevor AJ
      Ketamine, catecholamines, and uterine tone in pregnant ewes.
      or 5 mg/kg
      • Levinson G
      • Shnider SM
      • Gildea JE
      • deLorimier AA
      Maternal and foetal cardiovascular and acid-base changes during ketamine anaesthesia in pregnant ewes.
      of ketamine. In one study, fetal hypertension and bradycardia were abolished by use of ketamine in fetal sheep made acidotic by partial occlusion of the umbilical cord, which restricted blood flow; however, fetal blood flows to the heart, brain, and kidneys were not altered considerably.
      • Swartz J
      • Cumming M
      • Biehl D
      The effect of ketamine anaesthesia on the acidotic fetal lamb.
      Etomidate is a safe and effective induction agent for both mother and newborn during cesarean section

      Ionescu T, Besse TC, Smalhout B: Etomidate during caesarian section (abstract). Excerpta Medica International Congress Series No. 533, 1980, pp 318–319

      • Downing JW
      • Buley RJR
      • Brock-Utne JG
      • Houlton PC
      Etomidate for induction of anaesthesia at caesarean section: comparison with thiopentone.
      and provides a hemodynamically stable induction of anesthesia in cardiac patients.
      • Warner MA
      • Warner ME
      Anesthetic agents for cardiac surgery.
      Propofol rapidly and substantially crosses the human placenta at the time of cesarean section, without producing subsequent adverse effects on the newly delivered infant;
      • Dailland P
      • Cockshott ID
      • Lirzin JD
      • Jacquinot P
      • Jorrot JC
      • Devery J
      • Harmey JL
      • Conseiller C
      Intravenous propofol during cesarean section: placental transfer, concentrations in breast milk, and neonatal effects; a preliminary study.
      however, its place in cardiac anesthesia has yet to be determined. Benzodiazepines such as diazepam and midazolam are frequently used during the induction and maintenance of cardiac anesthesia.
      • Warner MA
      • Warner ME
      Anesthetic agents for cardiac surgery.
      Both drugs readily cross the placenta into the fetal circulation.
      • Bakke OM
      • Haram K
      • Lygre T
      • Wallem G
      Comparison of the placental transfer of thiopental and diazepam in caesarean section.
      • Cavanagh D
      • Condo CS
      Diazepam—a pilot study of drug concentrations in maternal blood, amniotic fluid and cord blood.
      • Bach V
      • Carl P
      • Ravlo O
      • Crawford ME
      • Jensen AG
      • Mikkelsen BO
      • Crevoisier C
      • Heizmann P
      • Fattinger K
      A randomized comparison between midazolam and thiopental for elective cesarean section anesthesia. III. Placental transfer and elimination in neonates.
      Diazepam in doses that ranged from 0.1 to 0.5 mg/kg did not appreciably alter UBF or maternal and fetal hemodynamics in pregnant sheep.
      • Mofid M
      • Brinkman III, CR
      • Assali NS
      Effects of diazepam on uteroplacental and fetal hemodynamics and metabolism.
      In addition, maternal and fetal pH and arterial oxygen tension remained unchanged.
      • Mofid M
      • Brinkman III, CR
      • Assali NS
      Effects of diazepam on uteroplacental and fetal hemodynamics and metabolism.
      Diazepam has been implicated in increasing the risk of cleft lip with or without cleft palate in humans,
      • Safra MJ
      • Oakley Jr, GP
      Association between cleft lip with or without cleft palate and prenatal exposure to diazepam.
      • Saxén I
      • Saxén L
      Association between maternal intake of diazepam and oral clefts (letter to the editor).
      but firm data are lacking.

      Inhalational Agents.

      “Minimal alveolar concentration” (MAC) is a term used to quantify the concentration of inhalational anesthetic that prevents movement in 50% of animals or patients in response to a painful or noxious stimulus.
      • Stevens WC
      • Kingston HGG
      Inhalation anesthesia.
      • Merkel G
      • Eger II, EI
      A comparative study of halothane and halopropane anesthesia: including method for determining equipotency.
      Progesterone has central nervous system sedating properties and probably accounts for at least a portion of the reduction in MAC during pregnancy, which for halothane and isoflurane is decreased by 25% and 40%, respectively.
      • Palahniuk RJ
      • Shnider SM
      • Eger II, EI
      Pregnancy decreases the requirement for inhaled anesthetic agents.
      Similarly, other central nervous system depressants may have increased potency, and doses may need to be adjusted accordingly.
      Nitrous oxide rapidly traverses the placenta, and fetal uptake is also rapid.
      • Marx GF
      • Joshi CW
      • Orkin LR
      Placental transmission of nitrous oxide.
      Although concerns exist that nitrous oxide might alter or impair synthesis of DNA,
      • Nunn JF
      • Chanarin I
      Nitrous oxide inactivates methionine synthetase.
      one recent study found no apparent cases of teratogenicity in more than 400 infants exposed to nitrous oxide in utero.
      • Crawford JS
      • Lewis M
      Nitrous oxide in early human pregnancy.
      In a study of pregnant rats and their offspring, no teratogenicity was noted after multiple prolonged exposures to 0.75 MAC halothane, enflurane, or isoflurane or after exposure to 75% nitrous oxide.
      • Mazze RI
      • Fujinaga M
      • Rice SA
      • Harris SB
      • Baden JM
      Reproductive and teratogenic effects of nitrous oxide, halothane, isoflurane, and enflurane in Sprague-Dawley rats.
      Nitrous oxide (75%), but not halothane, enflurane, or isoflurane, resulted in increased fetal loss. Another study that evaluated the effects of 24 hours of exposure to 75% nitrous oxide in rats on day 9 of pregnancy found significant increases in fetal resorption and structural abnormalities.
      • Mazze RI
      • Wilson AI
      • Rice SA
      • Baden JM
      Reproduction and fetal development in rats exposed to nitrous oxide.
      How these studies compare with an isolated, briefer exposure intraoperatively in humans is uncertain.
      The adverse fetal effects of halothane have been further evaluated in various laboratory animals. Pregnant hamsters exposed to 0.6% halothane and 60% nitrous oxide in oxygen for 3 hours on day 10 or 11 of gestation had fetuses with decreased weight and size; exposure on day 11 also resulted in an increased rate of fetal resorption.
      • Bussard DA
      • Stoelting RK
      • Peterson C
      • Ishaq M
      Fetal changes in hamsters anesthetized with nitrous oxide and halothane.
      Similar adverse effects on fetal size in mice have been described with prolonged administration of halothane,
      • Wharton RS
      • Mazze RI
      • Baden JM
      • Hitt BA
      • Dooley JR
      Fertility, reproduction and postnatal survival in mice chronically exposed to halothane.
      but another study failed to demonstrate any adverse effects of halothane on rats or rabbits.
      • Kennedy Jr, GL
      • Smith SH
      • Keplinger ML
      • Calandra JC
      Reproductive and teratologic studies with halothane.
      Teratologic effects were not demonstrated with halothane in two of these studies.
      • Mazze RI
      • Fujinaga M
      • Rice SA
      • Harris SB
      • Baden JM
      Reproductive and teratogenic effects of nitrous oxide, halothane, isoflurane, and enflurane in Sprague-Dawley rats.
      • Kennedy Jr, GL
      • Smith SH
      • Keplinger ML
      • Calandra JC
      Reproductive and teratologic studies with halothane.
      Prolonged administration of enflurane in low concentrations (200 parts per million) to female rats
      • Green CJ
      • Monk SJ
      • Knight JF
      • Doré C
      • Luff NP
      • Halsey MJ
      Chronic exposure of rats to enflurane 200 p.p.m.: no evidence of toxicity or teratogenicity.
      caused no fetal toxicity or teratogenicity. Prolonged exposure to 1,500 parts per million of enflurane also produced no detectable adverse effects.
      • Peters MA
      • Hudson PM
      Postnatal development and behavior in offspring of enflurane exposed pregnant rats.
      Because these are subanesthetic concentrations administered on a prolonged basis, extrapolation to clinical situations is difficult.
      Halothane and isoflurane have been extensively studied in pregnant sheep.
      • Palahniuk RJ
      • Shnider SM
      Maternal and fetal cardiovascular and acid-base changes during halothane and isoflurane anesthesia in the pregnant ewe.
      • Biehl DR
      • Tweed WA
      • Cote J
      • Wade JG
      • Sitar D
      Effect of halothane on cardiac output and regional flow in the fetal lamb in utero.
      • Biehl DR
      • Yarnell R
      • Wade JG
      • Sitar D
      The uptake of isoflurane by the foetal lamb in utero: effect on regional blood flow.
      At 1.5 MAC, neither agent decreased UBF despite mild decreases (up to 20%) in maternal BP.
      • Palahniuk RJ
      • Shnider SM
      Maternal and fetal cardiovascular and acid-base changes during halothane and isoflurane anesthesia in the pregnant ewe.
      UBF was maintained because of a decrease in uterine vascular resistance, and neither fetal acid-base balance nor oxygenation was altered by these concentrations of anesthetics.
      • Palahniuk RJ
      • Shnider SM
      Maternal and fetal cardiovascular and acid-base changes during halothane and isoflurane anesthesia in the pregnant ewe.
      At 2.0 MAC halothane or isoflurane, maternal BP, cardiac output, and UBF decreased substantially; fetal hypoxemia and acidosis occurred concurrently with pronounced decreases in fetal BP and heart rate.
      • Palahniuk RJ
      • Shnider SM
      Maternal and fetal cardiovascular and acid-base changes during halothane and isoflurane anesthesia in the pregnant ewe.
      In another study, a similar depth of halothane anesthesia caused no major changes in maternal BP, heart rate, oxygenation, and acid-base status, but fetal mean arterial pressure decreased significantly while acid-base status and oxygenation remained unchanged.
      • Biehl DR
      • Tweed WA
      • Cote J
      • Wade JG
      • Sitar D
      Effect of halothane on cardiac output and regional flow in the fetal lamb in utero.
      This same research group also demonstrated that maternal exposure to isoflurane at levels that approached 2.0 MAC produced fetal acidosis and decreased fetal cardiac output after 60 minutes even though no alterations in maternal hemodynamics, acid-base status, or oxygenation were noted.
      • Biehl DR
      • Yarnell R
      • Wade JG
      • Sitar D
      The uptake of isoflurane by the foetal lamb in utero: effect on regional blood flow.
      An earlier study in humans also suggested that fetal acid-base status is not appreciably altered at this level of anesthesia with halothane.
      • Cosmi EV
      • Marx GF
      The effect of anesthesia on the acid-base status of the fetus.
      Halothane alone
      • Swartz J
      • Cummings M
      • Pucci W
      • Biehl D
      The effects of general anaesthesia on the asphyxiated foetal lamb in utero.
      • Yarnell R
      • Biehl DR
      • Tweed WA
      • Gregory GA
      • Sitar D
      The effect of halothane anaesthesia on the asphyxiated foetal lamb in utero.
      or halothane and nitrous oxide
      • Swartz J
      • Cummings M
      • Pucci W
      • Biehl D
      The effects of general anaesthesia on the asphyxiated foetal lamb in utero.
      administered to pregnant ewes abolish the fetal response to asphyxia (that is, bradycardia and increased BP) but do not affect fetal oxygenation or acid-base status and do not seem to worsen fetal status.
      • Yarnell R
      • Biehl DR
      • Tweed WA
      • Gregory GA
      • Sitar D
      The effect of halothane anaesthesia on the asphyxiated foetal lamb in utero.

      Narcotics.

      Fentanyl and sufentanil citrate are the most commonly used narcotics in cardiac surgical procedures. They can decrease the beat-to-beat variability in FHR and potentially mask fetal distress. Pertinent adverse effects in the mother include a delay in gastric emptying, rigidity of the chest wall and a consequent difficulty with ventilation during induction of anesthesia, and postoperative respiratory depression. Neonatal rigidity of the chest wall has been reported after maternal administration of fentanyl prior to cesarean section.
      • Jarvis AP
      • Arancibia CU
      A case of difficult neonatal ventilation (letter to the editor).
      Thus, it must be assumed that substantial amounts of the drug cross the placenta.
      Long-term maternal administration of morphine in rats has been implicated in increasing the number of stillborns, increasing infant mortality, and decreasing the rate of growth in newborns.
      • Zagon IS
      • McLaughlin PJ
      Effects of chronic morphine administration on pregnant rats and their offspring.
      Exencephaly and skeletal abnormalities in the offspring of pregnant mice after administration of morphine early in gestation have been noted, but the one-time doses used in that study—100 to 500 mg/kg—were far in excess of clinical requirements.
      • Harpel Jr, HS
      • Gautieri RF
      Morphine-induced fetal malformations. I. Exencephaly and axial skeletal fusions.
      Similar studies that used supraclinical doses of morphine sulfate, heroin, methadone hydrochloride, and meperidine produced central nervous system teratology in hamsters.
      • Geber WF
      • Schramm LC
      Congenital malformations of the central nervous system produced by narcotic analgesics in the hamster.
      Heroin addiction in humans has been related to the underdevelopment of various fetal organs and low birth weights, events thought not to be totally the result of poor maternal nutrition.
      • Naeye RL
      • Blanc W
      • Leblanc W
      • Khatamee MA
      Fetal complications of maternal heroin addiction: abnormal growth, infections, and episodes of stress.
      Long-term use of methadone in humans, however, has not been shown to be associated with teratogenicity, even though infants of these mothers have low mean birth weights.
      • Blinick G
      • Jerez E
      • Wallach RC
      Methadone maintenance, pregnancy, and progeny.
      Prolonged administration of fentanyl,
      • Mazze RI
      • Fujinaga M
      • Baden JM
      Reproductive and teratogenic effects of nitrous oxide, fentanyl and their combination in Sprague-Dawley rats.
      • Fujinaga M
      • Stevenson JB
      • Mazze RI
      Reproductive and teratogenic effects of fentanyl in Sprague-Dawley rats.
      sufentanil,
      • Fujinaga M
      • Mazze RI
      • Jackson EC
      • Baden JM
      Reproductive and teratogenic effects of sufentanil and alfentanil in Sprague-Dawley rats.
      and alfentanil hydrochloride
      • Fujinaga M
      • Mazze RI
      • Jackson EC
      • Baden JM
      Reproductive and teratogenic effects of sufentanil and alfentanil in Sprague-Dawley rats.
      to pregnant rats did not produce apparent teratogenesis or adverse reproductive effects. In summary, “no direct linkage between the use of narcotics and the induction of specific congenital abnormalities” has been found in humans.
      • Fogel M
      Teratogenesis and drugs in pregnancy.

      Muscle Relaxants.

      Succinylcholine chloride
      • Drábková J
      • Crul JF
      • van der Kleijn E
      Placental transfer of 14C labelled succinylcholine in near-term Macaca mulatta monkeys.
      and pancuronium bromide
      • Duvaldestin P
      • Demetriou M
      • Henzel D
      • Desmonts JM
      The placental transfer of pancuronium and its pharmacokinetics during caesarian section.
      cross the placenta rapidly despite being quaternary ammonium compounds and greatly ionized at body pH. Pregnancy reduces plasma pseudocholinesterase levels,
      • Shnider SM
      Serum cholinesterase activity during pregnancy, labor and the puerperium.
      but this effect seldom prolongs maternal muscle paralysis substantially after administration of succinylcholine.
      • Blitt CD
      • Petty WC
      • Alberternst EE
      • Wright BJ
      Correlation of plasma cholinesterase activity and duration of action of succinylcholine during pregnancy.
      Vecuronium bromide
      • Demetriou M
      • Depoix J-P
      • Diakite B
      • Fromentin M
      • Duvaldestin P
      Placental transfer of Org NC45 in women undergoing caesarean section.
      does not cross the placenta as readily as does pancuronium. Atracurium besylate
      • Flynn PJ
      • Frank M
      • Hughes R
      Use of atracurium in caesarean section.
      and curare
      • Kivalo I
      • Saarikoski S
      Placental transfer of 14C-dimethyltubocurarine during caesarean section.
      cross the placenta poorly. When administered maternally, none of these agents has been implicated in producing adverse fetal effects.
      Curare, when injected intravenously into chick embryos, has been implicated in producing limb deformities, but this effect is probably due to contractures associated with limb immobility during paralysis rather than to a direct effect of curare.
      • Drachman DB
      • Coulombre AJ
      Experimental clubfoot and arthrogryposis multiplex congenita.
      Numerous published case reports and series describe injecting curare, pancuronium, and atracurium directly into the human fetus, either intramuscularly or intravenously, during intrauterine therapeutic procedures.
      • Moise Jr, KJ
      • Carpenter Jr, RJ
      • Deter RL
      • Kirshon B
      • Diaz SF
      The use of fetal neuromuscular blockade during intrauterine procedures.
      • Copel JA
      • Grannum PA
      • Harrison D
      • Hobbins JC
      The use of intravenous pancuronium bromide to produce fetal paralysis during intravascular transfusion.
      • De Crespigny LC
      • Robinson HP
      • Ross AW
      • Quinn M
      Curarisation of fetus for intrauterine procedures (letter to the editor).
      • Bernstein HH
      • Chitkara U
      • Plosker H
      • Gettes M
      • Berkowitz RL
      Use of atracurium besylate to arrest fetal activity during intrauterine intravascular transfusions.
      No adverse sequelae have been attributed to this practice.

      Inotropic and Vasoactive Drugs.

      UBF is not autoregulated and is directly proportional to the mean perfusion pressure and inversely proportional to uterine vascular resistance. The human myometrium has both α- and β-adrenergic receptors. Because the uterine vasculature is maximally dilated during pregnancy, α-adrenergic stimulation will increase uterine vascular resistance, and thus potentially decrease UBF, and may increase uterine tone. Although β-adrenergic stimulation has a minimal effect on uterine vascular resistance and blood flow, β-adrenergic agents, such as ritodrine, are effective in decreasing uterine tone.
      Ephedrine sulfate, an indirectly acting agent with mixed α- and β-adrenergic activity, is currently the drug of choice in treating transient episodes of maternal hypotension. In unanesthetized gravid ewes, UBF was unaffected when maternal BP was increased by 50% with use of ephedrine.
      • Ralston DH
      • Shnider SM
      • deLorimier AA
      Effects of equipotent ephedrine, metaraminol, mephentermine, and methoxamine on uterine blood flow in the pregnant ewe.
      Phenylephrine hydrochloride, a pure α-adrenergic agent, significantly decreases UBF
      • Ring G
      • Krames E
      • Shnider SM
      • Wallis KL
      • Levinson G
      Comparison of nitroprusside and hydralazine in hypertensive pregnant ewes.
      and increases uterine vascular resistance
      • Greiss Jr, FC
      • Van Wilkes D
      Effects of sympathomimetic drugs and angiotensin on the uterine vascular bed.
      when administered to gravid ewes in doses large enough to increase maternal BP by 20%. It is not known whether these adverse effects on uterine hemodynamics occur when phenylephrine is used to treat hypotension clinically.
      Dopamine hydrochloride is a mixed sympathomimetic agent with direct dopaminergic plus direct and indirect α- and β-adrenergic activity. In studies in which dopamine has been administered to near-term, unanesthetized ewes, conflicting results have occurred.
      • Blanchard K
      • Dandavino A
      • Nuwayhid B
      • Brinkman III, CR
      • Assali NS
      Systemic and uterine hemodynamic responses to dopamine in pregnant and nonpregnant sheep.
      • Callender K
      • Levinson G
      • Shnider SM
      • Feduska NJ
      • Biehl DR
      • Ring G
      Dopamine administration in the normotensive pregnant ewe.
      Dopamine was found to increase maternal BP and cardiac output, while concurrently increasing UBF, when infused in dosages that exceeded 5 μg/kg per min.
      • Blanchard K
      • Dandavino A
      • Nuwayhid B
      • Brinkman III, CR
      • Assali NS
      Systemic and uterine hemodynamic responses to dopamine in pregnant and nonpregnant sheep.
      Another study showed that dosages of more than 10 μg/kg per min were necessary to increase maternal cardiac output and BP; however, at such doses, UBF decreased significantly.
      • Callender K
      • Levinson G
      • Shnider SM
      • Feduska NJ
      • Biehl DR
      • Ring G
      Dopamine administration in the normotensive pregnant ewe.
      Infusions of dopamine at higher doses also produced fetal acidosis and a decrease in fetal oxygen tension.
      • Callender K
      • Levinson G
      • Shnider SM
      • Feduska NJ
      • Biehl DR
      • Ring G
      Dopamine administration in the normotensive pregnant ewe.
      Conflicting data exist on the effects of dopamine on UBF when hypotension resulting in decreased uterine perfusion is produced by spinal anesthesia in near-term ewes.
      • Rolbin SH
      • Levinson G
      • Shnider SM
      • Biehl DR
      • Wright RG
      Dopamine treatment of spinal hypotension decreases uterine blood flow in the pregnant ewe.
      • Cabalum T
      • Zugaib M
      • Lieb S
      • Nuwayhid B
      • Brinkman III, CR
      • Assali NS
      Effect of dopamine on hypotension induced by spinal anesthesia.
      One study demonstrated that dopamine returned BP and UBF to baseline values,
      • Cabalum T
      • Zugaib M
      • Lieb S
      • Nuwayhid B
      • Brinkman III, CR
      • Assali NS
      Effect of dopamine on hypotension induced by spinal anesthesia.
      whereas another study demonstrated that UBF further decreased even when maternal hypotension was corrected.
      • Rolbin SH
      • Levinson G
      • Shnider SM
      • Biehl DR
      • Wright RG
      Dopamine treatment of spinal hypotension decreases uterine blood flow in the pregnant ewe.
      Administration of dopamine and of dobutamine hydrochloride in the pregnant ewe has been compared.
      • Fishburne JI
      • Meis PJ
      • Urban RB
      • Greiss FC
      • Wheeler AS
      • James FM
      • Swain MF
      • Rhyne AL
      Vascular and uterine responses to dobutamine and dopamine in the gravid ewe.
      Both agents resulted in decreases in UBF. Dopamine produced variable changes in heart rate, whereas dobutamine consistently increased the heart rate. Mean arterial pressure increased after administration of dopamine but remained unchanged after administration of dobutamine. Although both agents increased uterine vascular resistance, the change was greatest with dopamine. In the gravid baboon, up to 40 μg/kg per min of dopamine had no appreciable effect on heart rate or UBF but significantly increased mean arterial pressure when infused at rates of more than 20 μg/kg per min.
      • Fishburne Jr, JI
      • Dormer KJ
      • Payne GG
      • Gill PS
      • Ashrafzadeh AR
      • Rossavik IK
      Effects of amrinone and dopamine on uterine blood flow and vascular responses in the gravid baboon.
      Epinephrine has been associated with decreased UBF,
      • Hood DD
      • Dewan DM
      • James III, FM
      Maternal and fetal effects of epinephrine in gravid ewes.
      • Greiss Jr, FC
      • Pick Jr, JR
      The uterine vascular bed: adrenergic receptors.
      apparently caused by its α-adrenergic activity. In one case report, however, an infusion of epinephrine was used to improve maternal hemodynamics after CPB, and fetal bradycardia resolved.
      • Lamb MP
      • Ross K
      • Johnstone AM
      • Manners JM
      Fetal heart monitoring during open heart surgery.
      Possibly, the improvement in maternal hemodynamics resulted in improved UBF, followed by an improvement in fetal well-being.
      Norepinephrine bitartrate, administered by infusion at 0.1 and 0.2 μg/kg per min to awake, normotensive gravid ewes, did not significantly alter mean arterial pressure, heart rate, or UBF, but infusion rates of 0.5 μg/kg per min or more produced significant increases in mean arterial pressures, decreases in heart rate, and decreases in UBF.
      • Wheeler AS
      • James III, FM
      • Meis PJ
      • Rose JC
      • Fishburne JI
      • Dewan DM
      • Urban RB
      • Greiss Jr, FC
      Effects of nitroglycerin and nitroprusside on the uterine vasculature of gravid ewes.
      These results confirmed those from an earlier study that had demonstrated decreased UBF and increased vascular resistance with use of norepinephrine.
      • Greiss Jr, FC
      • Van Wilkes D
      Effects of sympathomimetic drugs and angiotensin on the uterine vascular bed.
      Amrinone lactate (up to 40 μg/kg per min), administered to anesthetized gravid baboons, had no effect on mean arterial pressure, heart rate, or UBF.
      • Fishburne Jr, JI
      • Dormer KJ
      • Payne GG
      • Gill PS
      • Ashrafzadeh AR
      • Rossavik IK
      Effects of amrinone and dopamine on uterine blood flow and vascular responses in the gravid baboon.
      Although that study did not evaluate changes in cardiac output or systemic vascular resistance, the authors stated that preliminary data from a companion study indicated that increases in cardiac output occur with decreases in systemic vascular resistance.
      Digoxin readily crosses the placental membrane; therefore, maternal and fetal levels of the drug are similar.
      • Rogers MC
      • Willerson JT
      • Goldblatt A
      • Smith TW
      Serum digoxin concentrations in the human fetus, neonate and infant.
      Maintenance doses of digoxin used during pregnancy may need to be decreased after delivery because maternal serum digoxin levels increase significantly within 30 days after delivery.
      • Rogers MC
      • Willerson JT
      • Goldblatt A
      • Smith TW
      Serum digoxin concentrations in the human fetus, neonate and infant.
      The causes of this result are unclear, but increases in maternal blood volume and glomerular filtration rate during pregnancy seem to be at least partially responsible.
      Of importance, studies that have evaluated the effects of inotropic and vasoactive drugs have used animals with normal cardiac and circulatory systems. Conceivably, an inotropic or vasoactive agent that improves cardiac output and BP in the hemodynamically compromised patient will overcome potentially deleterious direct effects on the uterine vasculature.

      β-Blockers.

      Propranolol and other β-blockers are known to cross the placenta and have even been used successfully to treat fetal tachycardias.
      • Teuscher A
      • Bossi E
      • Imhof P
      • Erb E
      • Stocker FP
      • Weber JW
      Effect of propranolol on fetal tachycardia in diabetic pregnancy.
      Theoretically, the potential for an increase in uterine tone with nonselective β-blockers exists,
      • Otterson WN
      • Dunnihoo DR
      Cardiac disease.
      • Rubin PC
      Treatment of hypertension in pregnancy.
      but no studies have proved that a β1-receptor specific drug is preferable to propranolol. Intrauterine growth retardation, fetal bradycardia, fetal hypoglycemia, and premature labor have been anecdotally reported in pregnant women on long-term β-blocker regimens, but evidence for these effects in well-controlled studies is lacking.
      • Rubin PC
      Beta blockers in pregnancy (editorial).
      • Frishman WH
      • Chesner M
      Beta-adrenergic blockers in pregnancy.
      The prolonged use of β-blockers during pregnancy has been recently reviewed.
      • Rubin PC
      Beta blockers in pregnancy (editorial).
      • Frishman WH
      • Chesner M
      Beta-adrenergic blockers in pregnancy.
      • Beeley L
      Adverse effects of drugs in later pregnancy.
      • Rubin PC
      Beta-blockers in pregnancy.
      Esmolol hydrochloride, a β1-adrenergic selective antagonist with an elimination half-life of 9 minutes, has in the past few years gained prominence as a titratable and easy-to-manage infusion for the control of tachyarrhythmias or hypertension (or both). Nonspecific erythrocyte esterases are responsible for its metabolism; therefore, its duration of action is independent of renal or hepatic function. Recently, investigators have shown that esmolol rapidly crosses the placental membrane of gravid ewes and that metabolism is rapid in the fetus, as it is in the mother.
      • Östman PL
      • Chestnut DH
      • Robillard JE
      • Weiner CP
      • Hdez MJ
      Transplacental passage and hemodynamic effects of esmolol in the gravid ewe.
      FHR and BP decreased 12% and 7%, respectively, but fetal acid-base status remained unaltered.
      Labetalol hydrochloride, a nonselective β-adrenergic and selective α1-adrenergic blocking agent, is widely used in treating intraoperative and postoperative hypertension. It is safe for both the mother and the fetus in short-term and long-term therapy for hypertension.
      • Frishman WH
      • Chesner M
      Beta-adrenergic blockers in pregnancy.
      • MacPherson M
      • Broughton Pipkin F
      • Rutter N
      The effect of maternal labetalol on the newborn infant.
      • Michael CA
      Intravenous labetalol and intravenous diazoxide in severe hypertension complicating pregnancy.

      Vasodilators.

      Sodium nitroprusside and hydralazine hydrochloride were compared in the treatment of hypertension and decreased UBF induced by phenylephrine in the near-term pregnant ewe.
      • Ring G
      • Krames E
      • Shnider SM
      • Wallis KL
      • Levinson G
      Comparison of nitroprusside and hydralazine in hypertensive pregnant ewes.
      Both drugs were effective in returning the BP to control values, but hydralazine was more effective in restoring UBF toward control levels. No significant acid-base changes were noted in the fetus or the ewe with the different therapies. Nitroglycerin and nitroprusside in the awake gravid ewe are effective in treating norepinephrine-induced maternal hypertension and improving UBF, which is decreased as a result of α-adrenergic stimulation.
      • Wheeler AS
      • James III, FM
      • Meis PJ
      • Rose JC
      • Fishburne JI
      • Dewan DM
      • Urban RB
      • Greiss Jr, FC
      Effects of nitroglycerin and nitroprusside on the uterine vasculature of gravid ewes.
      Nitroprusside readily crosses the placental membrane in the ewe, and fetal levels approximate maternal levels of the drug.
      • Naulty J
      • Cefalo RC
      • Lewis PE
      Fetal toxicity of nitroprusside in the pregnant ewe.
      In that study, UBF was not considerably altered, but five of eight fetuses died in utero of cyanide toxicity after tachyphylaxis developed in the ewe. These five ewes received a mean dosage of 25 μg/kg per min of nitroprusside, far beyond the clinically acceptable dosage. A subsequent study showed that an infusion of nitroprusside at 2.3 μg/kg per min corrected norepinephrine-induced hypertension without adversely affecting either the fetus or the ewe and without producing lethal fetal levels of cyanide.
      • Ellis SC
      • Wheeler AS
      • James III, FM
      • Rose JC
      • Meis PJ
      • Shihabi Z
      • Greiss Jr, FC
      • Urban RB
      Fetal and maternal effects of sodium nitroprusside used to counteract hypertension in gravid ewes.
      Infusion of nitroprusside at rates less than 3 μg/kg per min has been used to treat gestational hypertension in humans without adversely affecting the fetus and without producing significant cyanide levels in fetal cord blood.
      • Stempel JE
      • O'Grady JP
      • Morton MJ
      • Johnson KA
      Use of sodium nitroprusside in complications of gestational hypertension.
      Nitroprusside, when used for deliberate hypotension during surgical correction of a cerebral aneurysm, has been found to be safe in pregnant humans.
      • Rigg D
      • McDonogh A
      Use of sodium nitroprusside for deliberate hypotension during pregnancy.
      Hydralazine is useful for treating maternal hypertension while maintaining an adequate cardiac output. Disadvantages of the drug include the propensity to produce a reflex tachycardia and the inability to titrate and “fine tune” the BP rapidly.

      Calcium Channel Blockers.

      Verapamil hydrochloride (a 0.2 mg/kg infusion administered during a period of 3 minutes) in awake pregnant ewes has been shown to decrease UBF by 25% 2 minutes after infusion.
      • Murad SHN
      • Tabsh KMA
      • Shilyanski G
      • Kapur PA
      • Ma C
      • Lee C
      • Conklin KA
      Effects of verapamil on uterine blood flow and maternal cardiovascular function in the awake pregnant ewe.
      Maternal BP decreased significantly only at 2 minutes, but maternal cardiac output and systemic vascular resistance did not change significantly from baseline at any time. After the infusion, UBF remained at least 10% below baseline for 30 minutes. In the healthy patient, these alterations in UBF may not be physiologically important to the fetus, but in the patient with a depressed cardiovascular system, the fetal consequences may be dire. Placental transfer of verapamil is limited in the pregnant ewe, but prolongation of the PR interval in the fetal heart still occurs; however, fetal BP and acid-base status are unchanged.
      • Murad SHN
      • Tabsh KMA
      • Conklin KA
      • Shilyanski G
      • Ziadlourad F
      • Kapur PA
      • Flacke WE
      Verapamil: placental transfer and effects on maternal and fetal hemodynamics and atrioventricular conduction in the pregnant ewe.
      Nifedipine does not significantly decrease UBF in unanesthetized pygmy goats, even though maternal BP decreases and maternal heart rate increases transiently.
      • Veille JC
      • Bissonnette JM
      • Hohimer AR
      The effect of a calcium channel blocker (nifedipine) on uterine blood flow in the pregnant goat.
      A combination of nifedipine and atenolol has been successfully used in the treatment of severe preeclampsia in humans without apparent adverse fetal effects.
      • Rubin PC
      • McCabe R
      • Low RAL
      Calcium channel blockade with nifedipine combined with atenolol in the management of severe pre-eclampsia (abstract).

      Antiarrhythmics.

      Certain aspects of digoxin and verapamil therapy have been previously discussed. Both drugs are frequently used in the treatment of maternal supraventricular tachycardias, such as atrial fibrillation and flutter. Both digoxin and verapamil are known to cross the placental barrier and have been used to treat fetal tachyarrhythmias.
      • Kerenyi TD
      • Gleicher N
      • Meller J
      • Brown E
      • Steinfeld L
      • Chitkara U
      • Raucher H
      Transplacental cardio-version of intrauterine supraventricular tachycardia with digitalis.
      • Owen J
      • Colvin EV
      • Davis RO
      Fetal death after successful conversion of fetal supraventricular tachycardia with digoxin and verapamil.
      • Wolff F
      • Breuker KH
      • Schlensker KH
      • Bolte A
      Prenatal diagnosis and therapy of fetal heart rate anomalies: with a contribution on the placental transfer of verapamil.
      Digoxin and verapamil have no known teratogenicity and are thought to be safe for use during pregnancy.
      • Rotmensch HH
      • Elkayam U
      • Frishman W
      Antiarrhythmic drug therapy during pregnancy.
      Lidocaine is the initial drug of choice for the treatment of ventricular arrhythmias. Long-term administration of lidocaine to female rats before and during gestation was associated with no adverse teratogenic or reproductive effects.
      • Fujinaga M
      • Mazze RI
      Reproductive and teratogenic effects of lidocaine in Sprague-Dawley rats.
      At therapeutic levels, it does not have adverse effects on UBF.
      • Biehl D
      • Shnider SM
      • Levinson G
      • Callender K
      The direct effects of circulating lidocaine on uterine blood flow and foetal well-being in the pregnant ewe.
      In the immature fetus of pregnant ewes, a constant infusion of lidocaine achieving serum levels similar to those in humans during antiarrhythmic therapy worsened the fetal response to asphyxia (that is, pH, mean arterial pressure, and blood flow to the brain and heart decreased further when lidocaine was added to a hypoxic insult).
      • Morishima HO
      • Pedersen H
      • Santos AC
      • Schapiro HM
      • Finster M
      • Arthur GR
      • Covino BG
      Adverse effects of maternally administered lidocaine on the asphyxiated preterm fetal lamb.
      In near-term pregnant ewes, however, the fetal response to asphyxia is not significantly altered by a maternal infusion of lidocaine.
      • Morishima HO
      • Santos AC
      • Pedersen H
      • Finster M
      • Tsuji A
      • Hiraoka H
      • Arthur GR
      • Covino BG
      Effect of lidocaine on the asphyxial responses in the mature fetal lamb.
      Procainamide hydrochloride can be used to terminate ventricular arrhythmias and, if the ventricular response rate has been controlled, to terminate atrial fibrillation and flutter. It crosses the placental membrane and has been used to treat fetal tachyarrhythmias.
      • Dumesic DA
      • Silverman NH
      • Tobias S
      • Golbus MS
      Transplacental cardioversion of fetal supraventricular tachycardia with procainamide.
      This drug does not seem to have teratogenic or adverse fetal effects.
      • Rotmensch HH
      • Elkayam U
      • Frishman W
      Antiarrhythmic drug therapy during pregnancy.
      Bretylium tosylate is the second or third choice in the treatment of ventricular flutter or fibrillation; it should be used when other agents such as lidocaine have failed. Teratogenicity in laboratory animals and fetal safety in pregnant females have not been established, but these unknown factors should not prevent the use of bretylium if needed in the treatment of ventricular arrhythmias.
      Maternal direct-current cardioversion should be used if indicated. Several reports have demonstrated the absence of apparent adverse effects on the fetus because minimal electrical energy will reach the fetus.
      • DeSilva RA
      • Graboys TB
      • Podrid PJ
      • Lown B
      Cardioversion and defibrillation.
      • Schroeder JS
      • Harrison DC
      Repeated cardioversion during pregnancy: treatment of refractory paroxysmal atrial tachycardia during 3 successive pregnancies.
      • Sussman HF
      • Duque D
      • Lesser ME
      Atrial flutter with 1:1 A-V conduction: report of a case in a pregnant woman successfully treated with DC countershock.
      • Vogel JHK
      • Pryor R
      • Blount Jr, SG
      Direct-current defibrillation during pregnancy.
      In one case report, cardioversion from paroxysmal atrial tachycardia to normal sinus rhythm was accomplished seven times in one patient during three pregnancies; a normal child was delivered with each pregnancy.
      • Schroeder JS
      • Harrison DC
      Repeated cardioversion during pregnancy: treatment of refractory paroxysmal atrial tachycardia during 3 successive pregnancies.

      Anticholinergics.

      Atropine readily crosses the placenta,
      • Kanto J
      • Virtanen R
      • Iisalo E
      • Mäenpää K
      • Liukko P
      Placental transfer and pharmacokinetics of atropine after a single maternal intravenous and intramuscular administration.
      • Kivalo I
      • Saarikoski S
      Placental transmission of atropine at full-term pregnancy.
      whereas glycopyrrolate, a quaternary ammonium compound, does not. Equichronotropic doses of atropine (0.01 mg/kg) and glycopyrrolate (0.005 mg/kg) did not affect FHR or variability in FHR even though the maternal heart rate was increased to a similar degree by both drugs.
      • Abboud T
      • Raya J
      • Sadri S
      • Grobler N
      • Stine L
      • Miller F
      Fetal and maternal cardiovascular effects of atropine and glycopyrrolate.
      This result seems to contradict earlier literature in which FHR and variability in FHR were affected; however, the doses of atropine used were larger than those that are clinically needed.
      • Hellman LM
      • Johnson HL
      • Tolles WE
      • Jones EH
      Some factors affecting the fetal heart rate.
      Glycopyrrolate is a more pronounced antisialagogue than is atropine and also may be useful in increasing gastric pH.
      • Baraka A
      • Saab M
      • Salem MR
      • Winnie AP
      Control of gastric acidity by glycopyrrolate premedication in the parturient.

      Agents That Decrease Gastric Acidity.

      Even early in pregnancy, the risk for pulmonary aspiration of acidic gastric contents during general anesthesia is increased.
      • Cheek TG
      • Gutsche BB
      Maternal physiologic alterations during pregnancy.
      Several pharmacologic measures are available to reduce the volume and acidity of the gastric contents. Antacids administered alone usually result in pHs of more than 2.5, but the overall gastric volume is usually increased because of the volume of antacid given.
      • Colman RD
      • Frank M
      • Loughnan BA
      • Cohen DG
      • Cattermole R
      Use of i.m. ranitidine for the prophylaxis of aspiration pneumonitis in obstetrics.
      • McAuley DM
      • Moore J
      • McCaughey W
      • Donnelly BD
      • Dundee JW
      Ranitidine as an antacid before elective caesarean section.
      • O'Sullivan G
      • Sear JW
      • Bullingham RES
      • Carrie LES
      The effect of magnesium trisilicate mixture, metoclopramide and ranitidine on gastric pH, volume and serum gastrin.
      Nonparticulate antacids such as 0.3 M sodium citrate (or the commercially available Bicitra) are preferred because particulate antacids have been associated with more severe pulmonary injury if aspirated.
      • Gibbs CP
      • Schwartz DJ
      • Wynne JW
      • Hood CI
      • Kuck EJ
      Antacid pulmonary aspiration in the dog.
      H2 blockers such as cimetidine hydrochloride
      • Hodgkinson R
      • Glassenberg R
      • Joyce III, TH
      • Coombs DW
      • Ostheimer GW
      • Gibbs CP
      Comparison of cimetidine (Tagamet®) with antacid for safety and effectiveness in reducing gastric acidity before elective cesarean section.
      and ranitidine hydrochloride
      • Colman RD
      • Frank M
      • Loughnan BA
      • Cohen DG
      • Cattermole R
      Use of i.m. ranitidine for the prophylaxis of aspiration pneumonitis in obstetrics.
      • McAuley DM
      • Moore J
      • McCaughey W
      • Donnelly BD
      • Dundee JW
      Ranitidine as an antacid before elective caesarean section.
      • O'Sullivan G
      • Sear JW
      • Bullingham RES
      • Carrie LES
      The effect of magnesium trisilicate mixture, metoclopramide and ranitidine on gastric pH, volume and serum gastrin.
      • Gillett GB
      • Watson JD
      • Langford RM
      Ranitidine and single-dose antacid therapy as prophylaxis against acid aspiration syndrome in obstetric practice.
      have proved to be effective in increasing the pH and decreasing the volume of gastric contents in parturients. Metoclopramide hydrochloride
      • Cohen SE
      • Jasson J
      • Talafre M-L
      • Chauvelot-Moachon L
      • Barrier G
      Does metoclopramide decrease the volume of gastric contents in patients undergoing cesarean section?.
      hastens gastric emptying and increases the tone of the lower esophageal sphincter; hence, regurgitation and pulmonary aspiration are less likely. The combination of metoclopramide and ranitidine was shown to result in smaller gastric volumes than when either of the agents was used singly.
      • O'Sullivan G
      • Sear JW
      • Bullingham RES
      • Carrie LES
      The effect of magnesium trisilicate mixture, metoclopramide and ranitidine on gastric pH, volume and serum gastrin.
      Cimetidine
      • Howe JP
      • McGowan WAW
      • Moore J
      • McCaughey W
      • Dundee JW
      The placental transfer of cimetidine.
      and ranitidine
      • McAuley DM
      • Moore J
      • McCaughey W
      • Donnelly BD
      • Dundee JW
      Ranitidine as an antacid before elective caesarean section.
      readily cross the placenta in parturients but have not been associated with adverse effects in the newborn.

      Anticoagulants.

      Heparin-produced systemic anticoagulation is necessary during CPB. Because heparin is a large polyionic molecule, it does not cross the placenta, and it has not been associated with teratogenicity or fetal hemorrhage. The long-term use of warfarin sodium and heparin during pregnancy has been reviewed elsewhere.
      • Otterson WN
      • Dunnihoo DR
      Cardiac disease.
      • McAnulty JH
      • Metcalfe J
      • Ueland K
      Heart disease and pregnancy.
      • De Swiet M
      Anticoagulants.
      • Hall JG
      • Pauli RM
      • Wilson KM
      Maternal and fetal sequelae of anticoagulation during pregnancy.
      • Ben Ismail M
      • Abid F
      • Trabelsi S
      • Taktak M
      • Fekih M
      Cardiac valve prostheses, anticoagulation, and pregnancy.
      • Oakley C
      Valve prostheses and pregnancy (editorial).

      Diuretics.

      Mannitol has been found to cross the placenta, is concentrated in fetal urine, and subsequently is present in amniotic fluid.
      • Basso A
      • Fernández A
      • Althabe O
      • Sabini G
      • Piriz H
      • Belitzky R
      Passage of mannitol from mother to amniotic fluid and fetus.
      • Bain MD
      • Copas DK
      • Landon MJ
      • Stacey TE
      In vivo permeability of the human placenta to inulin and mannitol.
      Fetal diuresis associated with furosemide has been demonstrated in studies of pregnant sheep, an indication that this diuretic crosses the placenta in substantial amounts.
      • Lumbers ER
      • Stevens AD
      The effects of frusemide, saralasin and hypotension on fetal plasma renin activity and on fetal renal function.
      Furosemide (60 mg) administered to women during the last trimester of normal pregnancies and in pregnancies with evidence of intrauterine growth retardation resulted in brisk fetal diuresis without apparent adverse fetal effects.
      • Wladimiroff JW
      Effect of frusemide on fetal urine production.
      In contrast, however, the inability to induce fetal diuresis with administration of furosemide has been reported in an animal study
      • Ross MG
      • Ervin MG
      • Leake RD
      Failure of Lasix to induce a fetal diuresis (letter to the editor).
      and in the growth-retarded fetus, even when renal and bladder function was apparently normal after delivery.
      • Rosenberg ER
      • Bowie JD
      Failure of furosemide to induce diuresis in a growth-retarded fetus.
      • Harman CR
      Maternal furosemide may not provoke urine production in the compromised fetus.

      Antibiotics.

      The teratogenic risks of most antibiotics have been recently reviewed.
      Safety of antimicrobial drugs in pregnancy.
      • Hawkins DF
      Antimicrobial drugs in pregnancy and adverse effects on the fetus.
      The following discussion deals with those antibiotics most likely to be used in the perioperative period for patients who have undergone a cardiac surgical procedure. The aminoglycosides have the potential for producing injury to the eighth cranial nerve, and prolonged administration of streptomycin sulfate to pregnant women for the treatment of tuberculosis has been shown to result in fetal ototoxicity.
      Safety of antimicrobial drugs in pregnancy.
      • Snider Jr, DE
      • Layde PM
      • Johnson MW
      • Lyle MA
      Treatment of tuberculosis during pregnancy.
      Data about potential fetal toxicity are lacking for the other aminoglycosides. The penicillins and cephalosporins have no known toxicity to the fetus and are probably safe.
      Safety of antimicrobial drugs in pregnancy.
      • Hawkins DF
      Antimicrobial drugs in pregnancy and adverse effects on the fetus.
      Vancomycin hydrochloride crosses the human placenta, but its use in pregnant women during the second and third trimesters recently was not associated with subsequent renal toxicity or hearing loss in infants.
      • Reyes MP
      • Ostrea Jr, EM
      • Cabinian AE
      • Schmitt C
      • Rintelmann W
      Vancomycin during pregnancy: does it cause hearing loss or nephrotoxicity in the infant?.
      Nevertheless, caution has been urged when vancomycin is used.
      Safety of antimicrobial drugs in pregnancy.

      Dantrolene.

      Administration of dantrolene sodium to two pregnant women before cesarean section resulted in good Apgar scores and caused no apparent adverse effects in either the neonates or the mothers.
      • Morison DH
      Placental transfer of dantrolene (letter to the editor).
      Maternal and cord venous blood samples were obtained at delivery, and the fetal:maternal dantrolene ratios were 0.29 and 0.51; thus, a substantial amount of dantrolene crossed the placental membrane. In another study,
      • Craft Jr, JB
      • Goldberg NH
      • Lim M
      • Landsberger E
      • Mazel P
      • Abramson FP
      • Stolte AL
      • Braswell Jr, ME
      • Farina JP
      Cardiovascular effects and placental passage of dantrolene in the maternal-fetal sheep model.
      dantrolene administered to gravid ewes produced no clinically significant hemodynamic or acid-base effects in either the mother or the fetus. Fetal dantrolene levels in this model were approximately 10% of the maternal level.

      BYPASS CONSIDERATIONS

      In 1958, Leyse and associates
      • Leyse R
      • Ofstun M
      • Dillard DH
      • Merendino KA
      Congenital aortic stenosis in pregnancy, corrected by extracorporeal circulation: offering a viable male infant at term but with anomalies eventuating in his death at four months of age—report of a case.
      were the first to use CPB for a cardiac surgical procedure in a pregnant patient. Since that initial experience, studies have shown that the pregnant patient apparently can tolerate the effects of CPB as well as can the nonpregnant patient,
      • Becker RM
      Intracardiac surgery in pregnant women.
      • Lapiedra OJ
      • Bernal JM
      • Ninot S
      • Gonzalez I
      • Pastor E
      • Miralles PJ
      Open heart surgery for thrombosis of a prosthetic mitral valve during pregnancy: fetal hydrocephalus.
      • Zitnik RS
      • Brandenburg RO
      • Sheldon R
      • Wallace RB
      Pregnancy and open-heart surgery.
      but the well-being of the fetus is less certain. In a multi-institutional review of CPB during cardiac operations before 1969, Zitnik and colleagues
      • Zitnik RS
      • Brandenburg RO
      • Sheldon R
      • Wallace RB
      Pregnancy and open-heart surgery.
      found that maternal mortality was 5% and associated fetal mortality was 33%. In a review of 23 cases of CPB during pregnancy published after 1969, Lapiedra and co-workers
      • Lapiedra OJ
      • Bernal JM
      • Ninot S
      • Gonzalez I
      • Pastor E
      • Miralles PJ
      Open heart surgery for thrombosis of a prosthetic mitral valve during pregnancy: fetal hydrocephalus.
      found only 1 fetal death and no maternal mortality. Becker
      • Becker RM
      Intracardiac surgery in pregnant women.
      surveyed members of the Society of Thoracic Surgeons for information about pregnancy and cardiac surgical procedures that necessitated CPB; among 68 cases found, 1 maternal death and 11 fetal deaths occurred. The risk to the fetus, which seems to be substantial, has been blamed on the unphysiologic and potentially harmful effects of CPB. Fetal mortality may also have been adversely influenced by the emergent nature of the surgical procedure and, in some cases, an unstable maternal status. Potentially adverse effects of CPB include changes in coagulation, alterations in the function of cellular and protein components of the blood, release of vasoactive substances from leukocytes, complement activation, particulate and air embolism, nonpulsatile flow, and hypotension. The actual effect of CPB on the fetus has not been studied in a clinically or experimentally controlled manner.
      The optimal flow for CPB in the pregnant patient is controversial, inasmuch as no controlled studies have been performed on pregnant patients or animals. Flows as low as 1.6 liters/min per m2 during normothermic CPB will avoid acidosis and manifestations of shock; however, CPB flows of 1.8 liters/min per m2 or more will provide adequate oxygen delivery for whole-body consumption of oxygen.
      • Kirklin JW
      • Barratt-Boyes BG
      Although the adequacy of oxygenation at the cellular level has been thought to be reflected in the mixed venous saturation, this assumption may not be totally true.
      • Kirklin JW
      • Barratt-Boyes BG
      CPB may contribute to an altered distribution of blood flow in comparison with the normal situation, and the result may be inadequate delivery of oxygen. Inadequate cellular oxygenation in various vascular beds can result in increased mixed venous saturations because of uneven distribution of blood flow at the capillary level. Ideally, delivery of oxygen should be sufficient for consumption of oxygen, and increasing consumption of oxygen occurs with increasing flow rates and delivery of oxygen.
      • Kirklin JW
      • Barratt-Boyes BG
      One explanation for this phenomenon is that perfusion to inadequately perfused vascular beds improves as total perfusion increases.
      Because of the increased cardiac output and consumption of oxygen associated with pregnancy, alterations of routine CPB may be necessary to ensure adequate perfusion and oxygenation to both the mother and the fetus. Although no studies have measured regional blood flows during CPB in pregnant animals, Lees and associates,
      • Lees MH
      • Herr RH
      • Hill JD
      • Morgan CL
      • Ochsner III, AJ
      • Thomas C
      • Van Fleet DL
      Distribution of systemic blood flow of the rhesus monkey during cardiopulmonary bypass.
      using radionuclide-labeled microspheres, found that UBF changed minimally during CPB. These results are interesting but cannot be extrapolated to pregnant humans.
      The choice of pulsatile or nonpulsatile CPB flow has not been fully evaluated, but pulsatile CPB has some theoretical advantages.
      • Korsten HHM
      • Van Zundert AAJ
      • Mooij PNM
      • De Jong PA
      • Bavinck JH
      Emergency aortic valve replacement in the 24th-week of pregnancy.
      A substantial reduction in delivery of oxygen to peripheral muscle has been shown to occur with nonpulsatile flow,
      • Page PA
      • Toung T
      A new probe for measurement of muscle pO2 and its use during cardiopulmonary bypass.
      and some investigators have suggested that decreased delivery of oxygen may possibly occur with the fetus.
      • Trimakas AP
      • Maxwell KD
      • Berkay S
      • Gardner TJ
      • Achuff SC
      Fetal monitoring during cardiopulmonary bypass for removal of a left atrial myxoma during pregnancy.
      Farmakides and associates
      • Farmakides G
      • Schulman H
      • Mohtashemi M
      • Ducey J
      • Fuss R
      • Mantell P
      Uterine-umbilical velocimetry in open heart surgery.
      used Doppler velocimetry during nonpulsatile CPB in a pregnant patient who underwent a cardiac operation and concluded that flow in the uterine artery was pulsatile. Careful analysis of their velocimetry tracing shows that pump artifact may have contributed to their observations. Although fetal hypoxia may possibly occur because of poor placental perfusion during nonpulsatile flow, other factors such as uterine arteriovenous shunts, spasm of the uterine artery, cannulation of the inferior vena cava obstructing venous drainage, and particulate or bubble emboli may also compromise the placental circulation.
      • Lamb MP
      • Ross K
      • Johnstone AM
      • Manners JM
      Fetal heart monitoring during open heart surgery.
      • Meffert WG
      • Stansel Jr, HC
      Open heart surgery during pregnancy.
      UBF is dependent on the perfusion pressure because the placental vasculature is maximally dilated, as mentioned earlier. A decrease in maternal BP even before the initiation of CPB may lead to fetal bradycardia, an indication of poor uteroplacental perfusion. At the onset of CPB, the mean arterial pressure usually declines abruptly as a result of a notable decrease in systemic vascular resistance, which may be the result of hemodilution
      • Gordon RJ
      • Ravin M
      • Daicoff GR
      • Rawitscher RE
      Effects of hemodilution on hypotension during cardiopulmonary bypass.
      or the release of vasoactive substances
      • Lees MH
      • Herr RH
      • Hill JD
      • Morgan CL
      • Ochsner III, AJ
      • Thomas C
      • Van Fleet DL
      Distribution of systemic blood flow of the rhesus monkey during cardiopulmonary bypass.
      (or both factors). Koh and colleagues,
      • Koh KS
      • Friesen RM
      • Livingstone RA
      • Peddle LJ
      Fetal monitoring during maternal cardiac surgery with cardiopulmonary bypass.
      who were the first to monitor FHR, noted that fetal bradycardia, frequently with a loss of beat-to-beat variability, commonly occurs at the onset of CPB, an indication of poor uteroplacental perfusion. Other investigators have since confirmed their findings.
      • Lamb MP
      • Ross K
      • Johnstone AM
      • Manners JM
      Fetal heart monitoring during open heart surgery.
      • Korsten HHM
      • Van Zundert AAJ
      • Mooij PNM
      • De Jong PA
      • Bavinck JH
      Emergency aortic valve replacement in the 24th-week of pregnancy.
      • Trimakas AP
      • Maxwell KD
      • Berkay S
      • Gardner TJ
      • Achuff SC
      Fetal monitoring during cardiopulmonary bypass for removal of a left atrial myxoma during pregnancy.
      • Mooij PNM
      • de Jong PA
      • Bavinck JH
      • Korsten HHM
      • Bonnier JJR
      • Berendes JN
      Aortic valve replacement in the second trimester of pregnancy: a case report.
      • Bahary CM
      • Ninio A
      • Gorodesky IG
      • Neri A
      Tococardiography in pregnancy during extracorporeal bypass for mitral valve replacement.
      • Levy DL
      • Warriner III, RA
      • Burgess III, GE
      Fetal response to cardiopulmonary bypass.
      • Eilen B
      • Kaiser IH
      • Becker RM
      • Cohen MN
      Aortic valve replacement in the third trimester of pregnancy: case report and review of the literature.
      • Werch A
      • Lambert HM
      • Cooley D
      • Reed CC
      Fetal monitoring and maternal open heart surgery (letter to the editor).
      Fetal bradycardia has been shown to respond frequently to an increase in the CPB pump flow, which also usually increases perfusion pressure.
      • Lamb MP
      • Ross K
      • Johnstone AM
      • Manners JM
      Fetal heart monitoring during open heart surgery.
      • Koh KS
      • Friesen RM
      • Livingstone RA
      • Peddle LJ
      Fetal monitoring during maternal cardiac surgery with cardiopulmonary bypass.
      • Werch A
      • Lambert HM
      • Cooley D
      • Reed CC
      Fetal monitoring and maternal open heart surgery (letter to the editor).
      As CPB continues, the release of endogenous catecholamines will increase the systemic vascular resistance, and perfusion pressure will increase
      • Kirklin JW
      • Barratt-Boyes BG
      or vasoactive drugs may be added to the bypass pump to increase vascular resistance. Increases in perfusion pressure, however, do not always prevent or alleviate fetal bradycardia. Trimakas and colleagues
      • Trimakas AP
      • Maxwell KD
      • Berkay S
      • Gardner TJ
      • Achuff SC
      Fetal monitoring during cardiopulmonary bypass for removal of a left atrial myxoma during pregnancy.
      described a persistent FHR of 80 to 100 beats/min for the duration of CPB despite a normal maternal acid-base status, normal temperature, and perfusion pressures that varied from 61 to 82 mm Hg. Lamb and associates
      • Lamb MP
      • Ross K
      • Johnstone AM
      • Manners JM
      Fetal heart monitoring during open heart surgery.
      found that, despite increasing flow on CPB, fetal bradycardia of 80 to 100 beats/min persisted, but the FHR returned to baseline after the maternal circulation was restored. Usually, improvement in the FHR occurs only after CPB is discontinued and maternal circulation is restored, at which time the FHR may transiently increase to 140 to 170 beats/min.
      • Trimakas AP
      • Maxwell KD
      • Berkay S
      • Gardner TJ
      • Achuff SC
      Fetal monitoring during cardiopulmonary bypass for removal of a left atrial myxoma during pregnancy.
      • Koh KS
      • Friesen RM
      • Livingstone RA
      • Peddle LJ
      Fetal monitoring during maternal cardiac surgery with cardiopulmonary bypass.
      This response may be a fetal compensatory mechanism after CPB or may reflect other influences that affect the fetus during CPB. Fetal bradycardia also occurs with normal maternal acid-base status.
      • Trimakas AP
      • Maxwell KD
      • Berkay S
      • Gardner TJ
      • Achuff SC
      Fetal monitoring during cardiopulmonary bypass for removal of a left atrial myxoma during pregnancy.
      • Eilen B
      • Kaiser IH
      • Becker RM
      • Cohen MN
      Aortic valve replacement in the third trimester of pregnancy: case report and review of the literature.
      As previously stated, an acceptable perfusion pressure does not necessarily ensure that placental perfusion will be adequate. Uterine contractility will influence UBF, and increased uterine activity can decrease placental perfusion.
      • Pedersen H
      • Finster M
      Anesthetic risk in the pregnant surgical patient.
      These events may explain continued fetal distress despite increased perfusion pressures and CPB pump flows. Mooij and colleagues
      • Mooij PNM
      • de Jong PA
      • Bavinck JH
      • Korsten HHM
      • Bonnier JJR
      • Berendes JN
      Aortic valve replacement in the second trimester of pregnancy: a case report.
      monitored uterine activity during CPB in a patient who underwent aortic valve replacement while 24 weeks pregnant. At the initiation of CPB, the FHR decreased to 60 beats/min with a lack of variability, repeated severe fetal decelerations occurred, and uterine contractions were detected. Other investigators have also described the onset of uterine contractions during CPB
      • Korsten HHM
      • Van Zundert AAJ
      • Mooij PNM
      • De Jong PA
      • Bavinck JH
      Emergency aortic valve replacement in the 24th-week of pregnancy.
      • Mooij PNM
      • de Jong PA
      • Bavinck JH
      • Korsten HHM
      • Bonnier JJR
      • Berendes JN
      Aortic valve replacement in the second trimester of pregnancy: a case report.
      • Bahary CM
      • Ninio A
      • Gorodesky IG
      • Neri A
      Tococardiography in pregnancy during extracorporeal bypass for mitral valve replacement.
      • Eilen B
      • Kaiser IH
      • Becker RM
      • Cohen MN
      Aortic valve replacement in the third trimester of pregnancy: case report and review of the literature.
      • Werch A
      • Lambert HM
      • Cooley D
      • Reed CC
      Fetal monitoring and maternal open heart surgery (letter to the editor).
      The cause of these contractions is uncertain, but some have been associated with hypothermia and rewarming.
      • Becker RM
      Intracardiac surgery in pregnant women.
      Some physicians have elected not to treat these contractions,
      • Eilen B
      • Kaiser IH
      • Becker RM
      • Cohen MN
      Aortic valve replacement in the third trimester of pregnancy: case report and review of the literature.
      whereas others have aggressively treated them with tocolytics such as ethanol,
      • Werch A
      • Lambert HM
      • Cooley D
      • Reed CC
      Fetal monitoring and maternal open heart surgery (letter to the editor).
      magnesium sulfate,
      • Mora CT
      • Grunewald KE
      Reoperative aortic and mitral prosthetic valve replacement in the third trimester of pregnancy.
      terbutaline,
      • Liu PL
      • Warren TM
      • Ostheimer GW
      • Weiss JB
      • Liu LMP
      Foetal monitoring in parturients undergoing surgery unrelated to pregnancy.
      • Conroy JM
      • Bailey MK
      • Hollon MF
      • Cooke JE
      • Baker III, JD
      Anesthesia for open heart surgery in the pregnant patient.
      and ritodrine.
      • Fishburne JI
      • Meis PJ
      • Urban RB
      • Greiss FC
      • Wheeler AS
      • James FM
      • Swain MF
      • Rhyne AL
      Vascular and uterine responses to dobutamine and dopamine in the gravid ewe.
      • Korsten HHM
      • Van Zundert AAJ
      • Mooij PNM
      • De Jong PA
      • Bavinck JH
      Emergency aortic valve replacement in the 24th-week of pregnancy.
      • Mooij PNM
      • de Jong PA
      • Bavinck JH
      • Korsten HHM
      • Bonnier JJR
      • Berendes JN
      Aortic valve replacement in the second trimester of pregnancy: a case report.
      Major complications, including pulmonary edema, hypotension, tachycardia, myocardial ischemia, hypokalemia, and hyperglycemia, can occur with β-adrenergic tocolytic therapy.
      Hypothermia is frequently used during CPB to improve myocardial preservation and to decrease systemic oxygen demands. The benefits and risks of hypothermia to the fetus during maternal surgical procedures are controversial. Little research has been performed in this area, and most of the information has been obtained from case reports or small series of patients.
      In pregnant dogs, cooling to 28°C resulted in increased uterine tone, a subsequent increase in uterine vascular resistance, and a decrease in UBF.
      • Assali NS
      • Westin B
      Effects of hypothermia on uterine circulation and on the fetus.
      No effect on fetal survival was noted; therefore, the authors suggested that fetal hypothermia might protect the fetus during hypoxia. Another study with pregnant ewes cooled to 29°C indicated that fetal distress occurred if maternal respiratory acidosis and hypoxia occurred.
      • Vandewater SL
      • Paul WM
      Observations on the foetus during experimental hypothermia.
      This study was not well designed or controlled, and the results need to be verified.
      Boatman and Bradford
      • Boatman KK
      • Bradford VA
      Excision of an internal carotid aneurysm during pregnancy employing hypothermia and a vascular shunt.
      described the excision of an internal carotid aneurysm in a pregnant woman (11 weeks) with use of hypothermia to 30.5°C. No apparent complications occurred, and a normal female infant was delivered at term. Profound hypothermia to a rectal temperature of 26.5°C was achieved for clipping of a cerebral arteriovenous malformation in a woman who was 4 months pregnant; subsequent term delivery of a healthy infant occurred.
      • Matsuki A
      • Oyama T
      Operation under hypothermia in a pregnant woman with an intracranial arteriovenous malformation.
      The authors who reported this case also reviewed the literature about hypothermic operations during pregnancy; they found that the lowest maternal temperatures achieved intraoperatively varied from 26.5°C to 32.5°C with gestational ages of 8 to 34 weeks. They also demonstrated that the fetus can tolerate even deep hypothermia in most instances, with subsequent uneventful pregnancies.
      Cardiac operations have been performed in pregnant patients at temperatures that have varied from 25°C to 37°C, with subsequent successful pregnancies.
      • Lamb MP
      • Ross K
      • Johnstone AM
      • Manners JM
      Fetal heart monitoring during open heart surgery.
      • Korsten HHM
      • Van Zundert AAJ
      • Mooij PNM
      • De Jong PA
      • Bavinck JH
      Emergency aortic valve replacement in the 24th-week of pregnancy.
      • Koh KS
      • Friesen RM
      • Livingstone RA
      • Peddle LJ
      Fetal monitoring during maternal cardiac surgery with cardiopulmonary bypass.
      • Levy DL
      • Warriner III, RA
      • Burgess III, GE
      Fetal response to cardiopulmonary bypass.
      • Mora CT
      • Grunewald KE
      Reoperative aortic and mitral prosthetic valve replacement in the third trimester of pregnancy.
      Pregnancies have continued successfully after profound maternal hypothermia. Aortic and mitral valve replacements were performed under hypothermic conditions (25°C) in a 28-year-old woman at 30 weeks of gestation.
      • Mora CT
      • Grunewald KE
      Reoperative aortic and mitral prosthetic valve replacement in the third trimester of pregnancy.
      Ten days after the mother was dismissed from the hospital, a healthy infant was born.
      At our institution, a 28-year-old woman who was 8 weeks pregnant underwent repair of tetralogy of Fallot with use of hypothermia to 24°C in combination with circulatory arrest. A normal infant was delivered at 35 weeks of gestation. Another case involved an 18-year-old patient who was 7 weeks pregnant and underwent accessory pathway ablation and tricuspid annuloplasty for Wolff-Parkinson-White syndrome and Ebstein's anomaly. The patient was cooled to 23°C without circulatory arrest. A premature, but healthy, 32-week-gestation infant was delivered subsequently. Cooper and co-workers,

      Cooper SC, Freeberg JR, Harp JR: Aortic valve replacement during pregnancy (abstract). In Program and Abstracts of the Society of Cardiovascular Anesthesiologists 8th Annual Meeting, 1986, p 103

      however, described a 26-week-pregnant woman who was cooled to 22°C during a cardiac operation. The FHR was 70 beats/min during this period, but the fetus was noted to be dead in utero 24 hours postoperatively. Perhaps this case indicates some gestational age-related risk for tolerance of hypothermia or CPB.
      Hypothermia has been considered a potential cause of fetal bradycardias, ventricular dysrhythmias, and fetal wastage associated with CPB, and some authors have recommended avoidance of hypothermia during cardiac operations in pregnant patients, if possible.
      • Becker RM
      Intracardiac surgery in pregnant women.
      • Conroy JM
      • Bailey MK
      • Hollon MF
      • Cooke JE
      • Baker III, JD
      Anesthesia for open heart surgery in the pregnant patient.
      Fetal bradycardia during hypothermic CPB may be due to fetal cooling and not to fetal hypoxia or distress.
      • Becker RM
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      • Eilen B
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      Aortic valve replacement in the third trimester of pregnancy: case report and review of the literature.
      Fetal bradycardia of 90 to 110 beats/min has also been associated with maternal hypothermia during urosepsis with no evidence of fetal distress.
      • Jadhon ME
      • Main EK
      Fetal bradycardia associated with maternal hypothermia.
      More importantly, the fetal heart tones gradually increased to 130 to 140 beats/min as the maternal temperature returned to normal. Hypothermia may actually protect the fetus by reducing fetal oxygen requirements,
      • Mora CT
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      Reoperative aortic and mitral prosthetic valve replacement in the third trimester of pregnancy.
      as proposed in early canine studies.
      • Assali NS
      • Westin B
      Effects of hypothermia on uterine circulation and on the fetus.

      POSSIBLE APPROACH FOR FUTURE CASES

      Obviously, close communication and consultation are imperative among the obstetrician or perinatologist, cardiologist, cardiac surgeon, and anesthesiologist in cases of CPB in pregnant patients. A neonatologist should be involved if the possibility of a cesarean section with delivery of a viable fetus exists. A plan for maternal and fetal care must be discussed by all members of the medical team, especially when the best interests of the patient potentially conflict with those of the fetus.
      No specific anesthetic technique or agents have proved to be superior to others, and anesthesiologists should use their technique of choice. CPB pump flows of at least 2.0 liters/min per m2 and a mean arterial pressure of 60 torr or more should be adequate for good placental perfusion. Pulsatile perfusion may provide additional benefit, but this factor has not been proved. Moderate hypothermia, such as 32°C, is probably safe. More profound hypothermia is compatible with fetal survival but may increase fetal arrhythmias and wastage. The FHR should be monitored if possible. CPB pump flows or mean arterial pressure can be increased if fetal bradycardia occurs. Although fetal bradycardia of any degree is worrisome, a FHR of less than 80 beats/min for more than 10 minutes is ominous, and we advocate cesarean section if fetal salvage is possible. These recommendations are simply guidelines because research data and clinical experience in this area are limited.

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