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Gastrointest Endoscopy Clin N Am

16 (2006) 1 – 31

Sedation and Analgesia for Gastrointestinal

Endoscopy during Pregnancy
Mitchell S. Cappell, MD, PhD, FACG
Division of Gastroenterology, Department of Medicine, Albert Einstein Medical Center,
Klein Professional Building, Suite 363, 5401 Old York Road, Philadelphia, PA 19141, USA

Although gastrointestinal endoscopy is recognized as a safe, well-tolerated,

and standard procedure in the general population [1–3], the risks, benefits, and
indications during pregnancy are less well known. In addition to the usual patient
risks, endoscopy during pregnancy raises the unique issue of fetal safety.
The fetal risks of endoscopy during pregnancy have been the subject of several
clinical studies [4–9] and clinical reviews [10–13]; however, a separate review of
the fetal safety of anesthetic medications is important and timely. First, anesthetic
medications comprise an important, if not the most important, risk factor to
the fetus during endoscopy, particularly during the first trimester [14–16].
Medications can be directly teratogenic or can indirectly cause fetal distress
secondary to effects on the mother such as cardiac arrhythmias [17–20], systemic
hypotension [17], and transient hypoxia [21]. Respiratory compromise and
hypoxia, from administered anesthetic medications [22], can be compounded at
esophagogastroduodenoscopy (EGD) or endoscopic retrograde cholangiopan-
creatography (ERCP) by vagally mediated bronchospasm, laryngeal impinge-
ment during esophageal intubation [19,21,22], and pulmonary aspiration of
gastric contents [22,23]. Second, analysis of fetal risks can help the physician
avoid, restrict, or replace potentially teratogenic endoscopic medications. This is
becoming more important because of the recent introduction of several alternative
anesthetic agents for endoscopy. Third, a physician who is well informed about

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the fetal risks of analgesic and sedative medications can advise and guide the
patient during informed consent. Fourth, review of standard principles and
practice guidelines can improve anesthetic safety during endoscopy (eg, by ma-
ternal assessment before endoscopy and maternal monitoring during endoscopy).
Fifth, malpractice judgments are sometimes astronomically large in cases of
poor fetal outcome [24]. Documentation of the relative safety of endoscopic
medications during pregnancy, when properly indicated and appropriately ad-
ministered, can prevent unnecessary litigation.
Knowledge about the safety of endoscopic anesthetics during pregnancy is,
however, incomplete. The published studies are retrospective. Despite current
uncertainties, the physician who evaluates a patient referred for gastrointestinal
endoscopy during pregnancy can be provided with guidelines. This article criti-
cally and comprehensively analyzes the fetal safety of endoscopic sedation
and analgesia.

Anesthesia for endoscopy

Sedation and analgesia are usually indicated for gastrointestinal endoscopic

procedures in the general population to reduce anxiety and minimize pain, except
for flexible sigmoidoscopy for which sedation and analgesia are optional. The
level of sedation varies according to the procedure; the most profound level of
sedation is needed for ERCP with sphincterotomy or other therapeutic procedures
[25]. These anesthesiologic principles also apply to endoscopy during pregnancy,
but administration of the minimal effective dose of sedative and analgesic is
emphasized. Thus, sedation and analgesia may be reasonably avoided altogether
for flexible sigmoidoscopy during pregnancy if so desired by the patient.
Various endoscopic procedures have been performed during pregnancy, par-
ticularly EGD, flexible sigmoidoscopy, and ERCP (Table 1; [4,5,9,26–35]).
Pregnant patients frequently suffer from gastrointestinal conditions that constitute
strong indications for endoscopy. More than 12,000 pregnant women per year in
America have a strong indication for EGD, such as acute upper gastrointestinal
bleeding. More than 6000 pregnant women per year have a strong indication for
sigmoidoscopy or colonoscopy, such as nonhemorrhoidal lower gastrointestinal
bleeding. About 1000 pregnant women per year have a strong indication for
therapeutic ERCP, such as complicated choledocholithiasis [7,36,37]. A prac-
ticing gastroenterologist, therefore, encounters a pregnant patient who has a
strong indication for gastrointestinal endoscopy about once a year.
Diagnostic and therapeutic endoscopy may be particularly valuable during
pregnancy because: (1) diagnosis by barium radiography is relatively contrain-
dicated because of radiation teratogenesis [38]; (2) prescription of gastrointestinal
drugs based on empirical data and without a definitive endoscopic diagnosis
is undesirable because of medication teratogenesis [39]; and (3) the alternative
therapy—gastrointestinal surgery—for active gastrointestinal bleeding or com-
sedation and analgesia during pregnancy 3

Table 1
Endoscopic procedures generally requiring anesthesia during pregnancy
Selected references for
Endoscopic procedure procedure during pregnancy
Diagnostic procedure
EGD [5]
Flexible sigmoidoscopy (anesthesia optional) [4]
Colonoscopy [4]
ERCP [26,27]
Endoscopic ultrasound [28,29]
Therapeutic procedure
EGD with variceal sclerotherapy or banding [5,30]
EGD with control of hemostasis [5,31]
EGD with endoscopic dilatation of a stricture [32]
ERCP with sphincterotomy [9]
ERCP with stent placement [33]
PEG [34,35]
Endoscopic ultrasound with drainage of a pancreatic pseudocyst [28,29]
Highly uncommon endoscopic procedures during pregnancy
ERCP with placement of a nasobiliary tube
Colonoscopy with polypectomy
Colonoscopy with endoscopic mucosal resection
EGD with endoscopic mucosal resection
Endoscopic ultrasound with celiac ganglion axis ablation
Abbreviations: EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancrea-
tography; PEG, percutaneous endoscopic gastrostomy.

plicated choledocholithiasis is undesirable because of the risk of fetal wast-

age [40].

Physiological changes during pregnancy: anesthesiologic and endoscopic


Abdominal assessment during pregnancy is modified by displacement of ab-

dominal viscera by the expanding gravid uterus [41]. In the nonpregnant patient,
external compression and detection of endoscopic transillumination in the right
lower quadrant help verify cecal intubation during colonoscopy. These signs can
be unreliable during advanced pregnancy because the cecum is displaced by the
enlarged gravid uterus [42]. However, visualization of the appendix and of the
ileocecal valve remain as reliable markers of cecal intubation during pregnancy.
In the nonpregnant patient, colonic overdistention from excessive air insufflation
during colonoscopy manifests as abdominal distention. This sign may be difficult
to recognize during advanced pregnancy because of the enlarged gravid uterus. In
the nonpregnant patient, external abdominal compression is often applied during
colonoscopy to facilitate cecal intubation. This compression should be applied
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gently and away from the uterus in patients who are in advanced pregnancy to
avoid uterine trauma.
The fetus is particularly sensitive to maternal hypoxia and hypotension [37].
For example, maternal hypotension from bleeding during pregnancy leads
to maternal cathecholamine release, which produces uterine vasoconstriction,
placental hypoperfusion, and potential fetal injury [43]. A relatively normal
maternal blood pressure does not guarantee fetal perfusion, and maternal tolerance
of transient hypoxia or hypotension does not guarantee fetal well being [43].
Maternal hypotension and hypoxia should, therefore, be avoided and aggres-
sively treated during endoscopy. Measures to avoid maternal hypotension during
endoscopy include adequate hydration before the procedure, transfusion of
packed erythrocytes (as necessary) for patients who present with gastrointestinal
bleeding, limited use of medications that can produce dehydration such as
diuretics, limited use of antihypertensive medications before the procedure, use of
the minimal effective dose of analgesics and sedatives during the procedure, and
avoidance of colonic overdistention during colonoscopy. Patients who receive
colonic lavage for colonoscopy should receive adequate hydration preprocedure.
Hypotension during the procedure should be treated by (1) prompt intravenous
hydration with normal saline or a similarly high osmolar solution, (2) a change to
the patient’s position to help drain blood from the lower extremities to perfuse
the vital organs, (3) restricted use of analgesics and sedatives, and (4) con-
sideration of aborting the endoscopic procedure. In particular, the colonoscopist
may be well advised to terminate a difficult and painful colonoscopy dur-
ing pregnancy.
The hematocrit is not a reliable indicator of bleeding severity in the general
population because of the lag between blood loss and hematocrit decline. The
hematocrit is an even less reliable indicator during pregnancy because of the
conflicting effects of intravascular fluid accumulation and increased total
erythrocyte mass during normal pregnancy [44,45]. The central venous pressure
is usually lower in the pregnant woman. Fluid, including transfusions of packed
erythrocytes when indicated, should be aggressively administered to pregnant
patients who undergo endoscopy for gastrointestinal bleeding because of the
extraordinary fetal sensitivity to hypoperfusion, the difficulty in assessing volume
status during pregnancy, and the usually satisfactory cardiac function of preg-
nant patients.
In the general population, patients are often placed in the supine position
during colonoscopy. The physician should avoid placing the pregnant patient
with gastrointestinal bleeding in the supine position during colonoscopy because,
in this position, the enlarged gravid uterus compresses the inferior vena cava,
decreases venous return, exacerbates maternal hypotension, and decreases uterine
perfusion [46]. Simply turning the patient to the left side to displace the uterus
may relieve this compression, improve venous return, and normalize the blood
pressure [41,46].
Maternal hypoxia during endoscopy is prevented by the administration of
supplemental oxygen by nasal cannulae, use of the minimal effective dose of
sedation and analgesia during pregnancy 5

sedatives and analgesics, optimization of cardiac and pulmonary status before the
procedure, avoidance of colonic overdistention during colonoscopy, avoidance
of oropharyngeal trauma during upper endoscopic intubation, aspiration of the
gastric lake during upper endoscopy, peroral aspiration as necessary to remove
oropharyngeal secretions, and placement of the patient in a decubitus position
with the patient’s head slightly elevated to prevent pulmonary aspiration.
Nasogastric aspiration in patients who have active upper gastrointestinal bleeding
before EGD helps prevent pulmonary aspiration during endoscopy and helps
clear the endoscopic field. This maneuver is particularly important during preg-
nancy because the pregnant state promotes nausea and vomiting, particularly
during the first trimester, as a result of the effects of gestational sex hormones
and gastric compression by the gravid uterus [47].
To reduce the risk of preterm uterine contractions or premature labor, avoid
mechanical trauma to the uterus during endoscopy, especially from looping
during colonoscopy, and avoid ischemic insult to the uterus from maternal
hypotension or hypoxia. Premature uterine contractions during endoscopy may
require tocolytics, such as magnesium sulfate or terbutaline [48,49].

Team approach

The endoscopic management of complicated gastrointestinal disease during

pregnancy, particularly symptomatic cholelithiasis, is improved by the formation
of a team that may include a gastroenterologist, obstetrician, anesthesiologist,
surgeon, and radiation physicist. Such a team is ideally located at tertiary medical
centers where the requisite experience and expertise is available. Pregnant pa-
tients who present to community hospitals with complicated gastrointestinal
disease may be referred to these tertiary medical centers.

Preprocedure anesthesiologic evaluation

Although gastroenterologists routinely administer sedation and analgesia for

endoscopy without anesthesiologic assistance in the general population, gastro-
enterologists should consider anesthesiologic consultation for pregnant patients
because of concern about medication teratogenicity. Anesthesiologic assistance
is recommended during pregnancy when the endoscopy is performed in the first
trimester because of the increased teratogenic risk; in the late third trimester or
with impending delivery because of the risk of premature labor; in a high-risk
pregnancy; for high-risk, invasive, and prolonged endoscopic procedures such as
therapeutic ERCP; and in a pregnant patient who has severe gastrointestinal
bleeding, choledocholithiasis complicated by ascending cholangitis, or other life-
threatening endoscopic indications.
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The anesthesiologist should obtain a brief history, perform a directed physical

examination, and check the critical laboratory tests to evaluate the safety of the
procedure and of sedative and analgesic medications (Box 1).
In the absence of an anesthesiologist, the endoscopist performs this directed
evaluation during the routine preprocedure patient evaluation. This evaluation is
used to exclude or identify contraindications to endoscopy, such as

severe electrolyte disorders

severe hyperglycemia
food in the stomach
blood in the stomach
fever or sepsis
significantly abnormal vital signs
uncooperative patient
unable to obtain valid consent
life-threatening arrhythmias or cardiac conduction disorders
significant coagulopathy
obstetric instability
preterm uterine contractions.

The evaluation is also used to guide triage decisions about the endoscopy
(Box 2).
The anesthesiologic evaluation concludes with a patient discussion about the
fetal risks, patient benefits, and patient choices regarding sedation and analgesia
during endoscopy, including:

known risks of anesthesiologic medications

unknown (potential) teratogenic risks of medications
alternatives to anesthesia during endoscopy
desired level of sedation and analgesia during endoscopy
written, signed, and witnessed consent.

The patient should be informed of the benefits and the small potential
teratogenic risks of endoscopic medications, but should be advised that the
potential fetal risks are incompletely characterized. This discussion is docu-
mented by a separate signed informed consent for anesthesia when performed by
an anesthesiologist, but is documented in the usual informed consent form for
endoscopy when performed by an endoscopist. Although the mother legally
makes all decisions concerning her endoscopy, the father may be apprised and
informed of the endoscopic decisions and findings, as appropriate.
sedation and analgesia during pregnancy 7

Box 1. Preprocedure anesthesiologic evaluation*

Medication & social history

Allergies to medications
Other allergies
Prescription medications
Nonprescription (over-the-counter) medications
Unregulated/alternative medications (herbal medicines)
Illicit medications (drug abuse)

Medical history

Liver disease
Easy bruisability/coagulopathy
Respiratory illnesses
Cardiovascular diseases
Anesthesiologic/surgical history
Obstetric history

Physical examination

Vital signs
Oxygen saturation
Oropharyngeal airway
Respiratory status
Cardiac examination
Abdominal examination
Mental status & neurologic evaluation

Laboratory tests

Routine electrolytes
Coagulation profile


American Society of Anesthesiology class

(Mallampati) airway class

* Performed by an anesthesiologist when in attendance at the en-

doscopic procedure or performed by a gastroenterologist, as part of
the routine preprocedure evaluation, when an anesthesiologist is not
in attendance.
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Box 2. Anesthesiology-related triage decisions for endoscopic


Anesthesiologist consultation for procedure

Obstetric consultation before procedure
Site of endoscopy: office-based endoscopy, versus ambulatory
surgery or endoscopy unit, versus in-hospital endoscopy
suite, versus intensive care unit
Timing of endoscopy: prompt (as scheduled) versus delayed
(until after patient stabilizes)
Preprocedure correction of electrolyte disorders
Preprocedure vitamin K administration
Preprocedure transfusion of packed erythrocytes
Preprocedure transfusion of other blood products
Preprocedure intravenous hydration
Preprocedure antibiotic prophylaxis
Ventilation: supplemental oxygen administration by nasal
cannulae, versus ventimask, versus continuous positive
airway pressure (CPAP), versus endotracheal intubation
Sedation and analgesia versus general anesthesia for procedure
Central venous pressure (CVP) monitoring during procedure
Fetal monitoring during procedure

Monitoring during endoscopy

Sedation and analgesia are rendered safer when the patient is monitored during
endoscopy (Box 3).
For example, pulse oximetry makes endoscopy safer by identifying hypoxic
patients (who should avoid endoscopy), by identifying patients who require
supplemental oxygen administration or endotracheal intubation before endos-
copy, and by alerting physicians to respiratory decompensation during endoscopy
[50]. Fetal monitoring is recommended during intra-abdominal surgery in the
third trimester [51,52]. Fetal monitoring is preferable during endoscopy, if
available, when fetal heart sounds become detectable [5]. The ambulatory
pregnant patient should be monitored postprocedure until the medication effects
wear off.

Medication teratogenicity

Medication teratogenicity is an inexact science. Safety in animal models does

not assure safety in humans because of species specificity, a lesson unfortunately
sedation and analgesia during pregnancy 9

Box 3. Recommended patient monitoring for endoscopy during



Continuous pulse oximetry

Intermittent (periodic) sphygmomanometry
Continuous respiratory rate monitoring
Continuous pulse monitoring
Continuous electrocardiographic monitoring


Fetal monitoring

Table 2
Difficulties assessing fetal safety of anesthetic medications
Problem Reason
Dearth of randomized clinical trials during Concern about poor outcomes and medico-legal
pregnancy liability by physicians, drug companies, and
Generally small and retrospective clinical trials Study medications often avoided during
pregnancy unless absolutely required
Drug studies have to be performed on a large Statistical analysis is required to detect a
population to detect a mild, but highly teroatogenic risk above the baseline risk of
clinically significant, teratogenic effect 1% to 3% [55,56]
Potential late toxicity from fetal exposure Fetal side effects may only manifest many years
after birth (eg, vaginal adenocarcinoma from
diethylstilbestrol exposure manifests after
puberty [57]; subtle neurodevelopmental
toxicity may manifest after starting school)
Fetal safety in animals does not necessarily Teratogenicity may be species specific
guarantee fetal safety in humans (eg, thalidomide safe in laboratory animals)
Fetal safety may critically depend upon Teratogenic risk greatest during organogenesis
maternal date of exposure in the first trimester
Fetal safety may depend upon route, dosage, Drug studies often lump together patients who
duration of exposure, or diluent of receive different dosages or other important
administered drug differences in drug administration during
Drug safety in newborn does not guarantee Very different physiologic considerations
safety to fetus
Confounding variables that can potentiate drug For example, the underlying illness for which
teratogenicity are typically not analyzed in the drug is prescribed can increase the terato-
drug studies genic rate above the baseline spontaneous
teratogenic rate
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Box 4. General principles and precautions concerning sedation and

analgesia for gastrointestinal endoscopy during pregnancy

Use smallest effective dose

Minimize procedure time to minimize the need for anesthetics
and sedatives
Substitute less invasive and shorter procedure, if possible, to
decrease intraprocedural medication use (eg, flexible
sigmoidoscopy for colonoscopy)
Terminate poorly tolerated procedures to avoid excessive
sedative or analgesic doses
Preferably use pregnancy category B instead of pregnancy
category C drugs, unless there is no effective alternative to
the category C drug
Avoid category D drugs
Do not use category X drugs
Avoid optional drugs
Contact pharmacologist or perform literature review as
necessary regarding drug teratogenicity
Consider anesthesiologist referral for administering analgesia
and sedation, particularly in more complicated, longer, or
higher-risk procedures (eg, therapeutic endoscopic
retrograde cholangiopancreatography)
Avoid use of drugs during the first trimester if possible (ie, defer
endoscopy when possible until after the first trimester)
Avoid use of drugs during active labor if possible (ie, defer
endoscopy to postpartum when possible)
Consider performing endoscopy in a hospital endoscopy suite
rather than private office during pregnancy to facilitate
treatment of procedure complications, including
medication side effects
Obtain fully informed and written consent that includes fetal risks
of procedure because of medications or other causes. Involve
patients in decisions on potentially fetotoxic medications
Refer patient who has a complicated clinical course and a very
high-risk endoscopy to an experienced endoscopist at a
tertiary medical center
Avoid antagonists to analgesic or sedative drugs. Use these
antagonists only when strongly indicated to treat an
analgesic or sedative overdose
Monitor the pregnant patient by continuous pulse oximetry and
electrocardiography, and by intermittent sphygmomanometry
Consider fetal monitoring during endoscopy, if available
sedation and analgesia during pregnancy 11

learned with thalidomide [53,54], and because physicians are reluctant to perform
and patients are reluctant to enroll in therapeutic clinical trials during pregnancy
(Table 2; [55–57]). Despite outstanding contributions by Briggs and coworkers
[58], and by Heinonen and colleagues [59], clinical studies of drug teratogenicity
during the first trimester, when available, are usually small and retrospective.
Historically, teratogenic effects have been appreciated late, unless they were large
or highly unusual. Thalidomide teratogenicity took years to appreciate despite
an extremely large (one in three) and highly unusual (phocomelia) teratogenic
effect [58].
Nonetheless, the existing data, even though mostly retrospective, nonrandom-
ized, and poorly controlled, provide crude estimates of drug teratogenicity. A

Table 3
Common complications related to anesthesia for endoscopy
Complication Identification Prevention/treatmenta
Hypotension Periodic sphygmomanometry Gradually administer narcotics and
sedatives with dosage titrated to effect;
administer fluids; transfuse as neces-
sary before endoscopy; avoid colonic
overdistention during colonoscopy
Hypoxia Pulse oximetry Gradually administer narcotics and
sedatives with dosage titrated to effect;
administer supplemental oxygen by
nasal cannulae; endotracheal intubation;
position head by manual pressure
on lower jaw
Hypoventilation Respiratory rate monitoring, Reversal agents for narcotics or seda-
pulse oximetry tives; stimulate patient; carefully
observe patient
Bradycardia Electrocardiographic monitoring Avoid colonic overdistention with air
during colonoscopy; avoid excessive
sedation or analgesia
Seizures Direct observation by nurse or Terminate procedure; correct electrolyte
anesthesiologist monitoring patient disorders; avoid hypoxia; antiseizure
during procedure drugs; seizure precautions
Aspiration Pulse oximetry, direct observation Suction oropharynx during procedure;
pneumonia place head to avoid pharyngeal aspira-
tion; consider prophylactic endotra-
cheal intubation for severe, active,
upper gastrointestinal hemorrhage
Angina Electrocardiographic monitoring, Avoid prolonged, difficult, and painful
direct observation endoscopy; antianginal medications;
cardiac stabilization before procedure
Premature uterine Fetal monitoring Tocolytics, avoid excessive uterine
contractions pressure, obstetric consultation, termi-
nate difficult and painful procedures
Severe endoscopic complications may require aborting the endoscopic procedure.
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Table 4
Food and Drug Administration categories of fetal risk from drugs administered during pregnancy
Category Fetal risk
A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester
(and there is no evidence of a risk in later trimesters), and the possibility of fetal harm
appears remote.
B Either animal reproduction studies have not demonstrated a fetal risk but there are no
controlled studies in pregnant women, or animal-reproduction studies have shown an
adverse effect (other than a decrease in fertility) that was not confirmed in controlled
studies in women in the first trimester (and there is no evidence of a risk in later
C Either studies in animals have revealed adverse effects on the fetus (teratogenic,
embryocidal, or other) and there are no controlled studies in women, or studies in
women and animals are not available. Drugs should be given only if the potential
benefit justifies the potential risk to the fetus.
D There is positive evidence of human fetal risk, but the benefits from use in pregnant
women may be acceptable despite the risk (eg, if the drug is needed in a life-
threatening situation or for a serious disease for which safer drugs cannot be used or
are ineffective).
X Studies in animals or humans have demonstrated fetal abnormalities, or there is
evidence of fetal risk based on human experience or both, and the risk of the use of
the drug in pregnant women clearly outweighs any possible benefit. The drug is
contraindicated in women who are or may become pregnant.

large, retrospective study that shows no teratogenicity strongly suggests that the
studied drug is not a major teratogen. Several concurring studies strengthen this
conclusion. Even a large study that shows a small, but statistically significant,
increase in congenital malformations after in utero drug exposure can suggest
that the drug is not a major teratogen: the reported association may be caused
by confounding variables, such as the underlying illness for which the drug
was administered.
General considerations about drug administration to the pregnant patient dur-
ing endoscopy are summarized in Box 4.
The identification and treatment of common endoscopic complications related
to anesthesia are summarized in Table 3. The Food and Drug Administration
(FDA) provides a useful classification of fetal risk of medications (Table 4). The
simplicity of this classification often belies the underlying complex, conflicting,
and controversial animal and clinical data. This classification should be used in
conjunction with clinical experience and knowledge of the relevant literature. The
following review considers the fetal risk of individual sedatives and analgesics.
Clinical studies on the overall fetal safety of endoscopy during pregnancy [4–9]
are omitted here, even though the overall endoscopic risks include the risks of
medications; these studies are reviewed in other articles. The reader is also
referred to the article on upper endoscopy during pregnancy for a review of
antibiotic prophylaxis for endoscopy during pregnancy.
sedation and analgesia during pregnancy 13

Sedative and analgesic medications administered by endoscopists

Meperidine (category B)

Meperidine, an opiate analgesic, has been commonly administered during

gastrointestinal endoscopy. Meperidine is rapidly transferred across the human
placenta after intramuscular injection [60], or intravenous administration [58].
Peak cord blood concentrations average about 75% of maternal plasma levels
[61]. Meperidine is metabolized in humans to normeperidine, which has a long
half-life. Repeated, high-dose, and prolonged administration of meperidine can
cause progressive accumulation of normeperidine, and produce toxic effects of
maternal respiratory depression and seizures [62]. Meperidine, unlike heroin or
methadone, has not been associated with an acute opioid withdrawal syndrome in
neonates born to addicted mothers, a syndrome that is characterized by irritability,
tremors, hypertonicity, altered gastrointestinal function, respiratory distress, and
occasionally seizures [63].
Two large studies revealed no teratogenicity from meperidine administration
during the first trimester. In the Collaborative Perinatal Project, meperidine
was not teratogenic in a study of 268 mothers who were exposed in the first
trimester, except that six of the infants with in utero exposure had inguinal
hernias [59]. In a surveillance study of Michigan Medicaid recipients, 3 of
62 newborns who had been exposed in utero during the first trimester had major
congenital defects; the unexposed control group had the same rate of congenital
defects [58].
Physicians have extensive experience prescribing meperidine during labor
[62,64–66]. Meperidine is preferred over morphine for obstetric analgesia be-
cause it crosses the fetal blood–brain barrier much more slowly [62]. Maternal
meperidine administration during delivery depresses neonatal respiration for
several hours thereafter because normeperidine, its active metabolite, is slowly
metabolized [67,68]. Meperidine may impair neonatal neuropsychologic func-
tions, such as attention and social responsiveness, during the first few weeks of
life [69–74]; these effects disappear with time [75]. Children whose mothers
received meperidine during labor had similar psychological, physical, and
intellectual parameters at 5 years of age as compared with children without in
utero exposure [76,77]. In utero meperidine exposure during labor does not
increase the risk of childhood cancer [78].
Meperidine can cause diminished fetal heart beat variability for about 1 hour
after maternal intravenous administration [79,80]. Generally, diminished cardiac
variability is a sign of fetal distress, such as fetal acidosis or hypoxemia, but the
effect produced by a single small-to-medium dose of meperidine is reversible,
transient, and not a poor prognostic indicator [81]. In one recent study of
407 pregnant women, women who received meperidine during delivery had a
worse neonatal outcome than pregnant women who received placebo, as mea-
sured by neonatal Apgar scores, umbilical artery acidosis, and neonatal intensive
care unit admission [82].
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Meperidine is rated a category B drug during pregnancy, except for a rating of

D when used for prolonged periods and at high doses at term [58]. It is preferred
to diazepam or midazolam as an endoscopic medication during pregnancy.
Meperidine dosage should be titrated to produce calmness, relaxation, and mild
analgesia without somnolence. Dosage should be restricted to 50 or 75 mg during
routine endoscopy.

Fentanyl (category C)

Fentanyl, a potent synthetic narcotic agonist, is increasingly used as an alter-

native to meperidine during endoscopy because of a faster onset of action and a
shorter recovery time [83]. Fentanyl was not teratogenic, but was embryocidal, in
rats who were administered 0.3 times the maximal human equivalent dose for
prolonged periods [84,85]. In humans, fentanyl crosses the placenta to the fetus
In numerous clinical studies, maternal fentanyl administration during labor
produced no neonatal toxicity [88–91]. For example, one study that compared
137 women who were administered fentanyl during labor with 112 women who
did not require any epidural or narcotic analgesia during labor, reported no
differences in newborn outcomes such as neonatal respiratory rate, Apgar score,
heart rate, blood pressure, neurologic status, and overall health [91]. In multiple
studies, addition of fentanyl to bupivacaine for spinal anesthesia during delivery
revealed no adverse effects on neonatal respiratory rate or neurobehavioral scores
In single case reports, fentanyl has, however, been associated with respiratory
depression [94], respiratory muscle rigidity [95], or opiate withdrawal that lasted
for several days after birth in an addicted mother [96]. Fentanyl, like meperidine,
can decrease fetal heart rate variability without causing fetal hypoxia [15,62].
Fentanyl is rated a risk category C during pregnancy, except for a rating of D if
used for prolonged periods or high doses at term [58,85]. The accumulated data
suggest that fentanyl may be used in low dosage for endoscopy during pregnancy.

Diazepam (category D)

Benzodiazepines, including diazepam and midazolam, are commonly admin-

istered before gastrointestinal endoscopy to reduce anxiety, induce brief amnesia,
and produce muscle relaxation. Diazepam rapidly crosses the placenta and
accumulates in the fetal circulation at levels equal to, or higher than, maternal
serum levels [97–99].
Diazepam administration to pregnant mice was associated with cleft palates in
their offspring [100]. Several studies suggested an association between diazepam
use during pregnancy and neonatal cleft lips or palates in humans [101–104]. For
example, in 1975, Safra and Oakley [105] reported in a retrospective study of
278 mothers, that mothers of children who had a cleft lip or palate had a fourfold
sedation and analgesia during pregnancy 15

increased rate of diazepam use during the first trimester as compared with
mothers of children with other congenital defects. These same investigators,
however, concluded from a review of the literature in 1976 that diazepam had not
been proven to cause oral clefts, and even if this relationship existed, the risk of
neonatal oral clefts from in utero exposure was only about 0.4% [106].
More recent studies have demonstrated no association between diazepam and
oral clefts [16,107–109]. No association was detected in a study that compared
611 infants who had oral clefts with 2498 infants who had other congenital
defects [16], or in a study that compared 355 infants who had oral clefts with
11,073 healthy infants [110]. No oral clefts occurred in the offspring of
80 mothers who used frequent, high-doses of diazepam during pregnancy [111].
The current consensus is that diazepam does not cause a significant risk of oral
clefts [112,113].
Other studies raised a possible association between diazepam exposure and
other congenital abnormalities. An association with congenital inguinal hernia
was reported in two studies [114,115]; cardiac defects and pyloric stenosis were
reported in a study that compared the rate of diazepam exposure among 1427
malformed newborns with 3001 healthy controls [115]; and Mobius syndrome
(sixth and seventh nerve palsies) was reported after in utero diazepam exposure in
one case report [116]. These associations are unconfirmed. In a study from the
Israeli Teratogen Service, 11 (3.1%) of 355 infants who experienced in utero first
trimester exposure to a benzodiazepine, including diazepam in 25% of cases, had
major congenital malformations compared with 10 (2.6%) of 382 unexposed
control infants [117]. A meta-analysis of nine cohort studies revealed no as-
sociation of diazepam with major malformations; whereas, a meta-analysis of
nine case-controlled studies showed an association with major malformations
(odds ratio 3.01, 95% confidence interval, 1.32–6.84) [118].
Several reports raised a possible association between frequent, high-dose
diazepam administration during pregnancy and neonatal mental retardation or
neurologic defects. For example, in one study, seven mothers who had ingested
high doses of diazepam during pregnancy had mentally retarded infants
[119,120]. Several investigators reported that high doses of diazepam adminis-
tered during labor may cause the floppy infant (overdose) syndrome characterized
by hypotonia, lethargy, and sucking difficulties [121–123], and a neonatal
withdrawal syndrome characterized by intrauterine growth retardation, tremors,
impaired temperature homeostasis, irritability, hypertonicity, diarrhea, vomiting,
and vigorous sucking [124,125]. This neonatal withdrawal syndrome seems to be
biologically plausible because chronically habituated pregnant women can
develop similar symptoms after abrupt diazepam cessation [126]. The risk of
either neonatal syndrome is increased by prolonged diazepam use. Generally,
infants gradually recover from the floppy infant syndrome as diazepam is
metabolized and disappears from the neonatal circulation.
Diazepam is categorized as a class D drug during pregnancy, and its use
should be carefully restricted during endoscopy, particularly during the first
trimester [58]. However, some recent experience suggests that it may be safer
16 cappell

during pregnancy than previously appreciated when administered at a low dose

for a brief period [127].

Midazolam (category D)

Many endoscopists prefer midazolam to diazepam for endoscopy because of

faster onset time and faster recovery time, more intense transient antegrade
amnesia, and lower risk of thrombophlebitis [128]. Administration of 10 and
5 times the maximal recommended human equivalent dose in pregnant rats and
rabbits, respectively, revealed no teratogenicity [85]. Midazolam crosses the
human placenta, but fetal serum levels rise to only one-third to two-thirds of
maternal serum levels after oral, intramuscular, or intravenous maternal ad-
ministration [129,130].
Several studies suggested that maternal midazolam administration during
parturition transiently depresses neonatal respiration [131–134], and neuro-
behavioral responsiveness [133]. Three of 19 infants whose mothers had received
midazolam during cesarean section had transient neurobehavioral abnormalities
in body temperature, body tone, and arm recoil [133]. In a controlled study of
52 infants, the infants who were exposed to midazolam during cesarean section
had lower Apgar scores at 1 minute after birth compared with unexposed controls
[131]. Another study confirmed these results [135]. These sedative effects are
attributable to direct neonatal effects of midazolam and should disappear after
drug elimination. Two other studies, however, reported no adverse effects in
30 and 20 newborns whose mothers received midazolam during parturition
Other than endoscopic studies [4,5], no published reports have analyzed the
effects of first or second trimester fetal exposure [58]. Midazolam was, however,
successfully used for patient sedation during intrafallopian gamete transfer with
subsequently normal pregnancies in a small clinical series [138]. This
benzodiazepine has not been associated with oral clefts.
This drug is classified a risk factor D during pregnancy [85], but seems to be
preferable to diazepam because of the potential, albeit unlikely, association
between diazepam and oral clefts and neonatal neurobehavioral abnormalities.
Because of a similar mechanism of action as diazepam, midazolam should be
used cautiously and in low doses during pregnancy, particularly during the first
trimester. Dosage should be titrated to an end point of relaxation and calmness
without somnolence.

Lidocaine (category B)

Lidocaine, an aminoethylamide local anesthetic, is often applied topically to

the oropharynx before EGD or ERCP to decrease the gag reflex and alleviate
oropharyngeal discomfort during endoscopic intubation. Lidocaine is occasion-
ally applied topically to the anus to relieve pain from anal conditions, especially
hemorrhoids, during flexible sigmoidoscopy or colonoscopy. Anesthesiologists
sedation and analgesia during pregnancy 17

sometimes use intravenous lidocaine in combination with intravenous propofol

for sedation and analgesia.
No fetal harm occurred after pregnant rats received 6.6 times the maximal
recommended equivalent human dose [85]. Lidocaine rapidly crosses the
placenta in humans [139]. Epidural lidocaine administration during parturition
resulted in mild transient neurologic depression of the newborn in some studies
[140], but not others [141]. The neurologic depression at birth, as evidenced by
low Apgar scores, was associated with very high neonatal serum levels of
lidocaine after maternal exposure during delivery [142]. Six cases of fetal
bradycardia or tachycardia were noted after 12 women received paracervical
lidocaine block during delivery [143]. Accidental lidocaine injection into the fetal
scalp during attempted local infiltration for episiotomy led to apnea and fixed and
dilated pupils 15 minutes after birth, and convulsions 1 hour after birth [144]. The
infant subsequently developed normally.
The current consensus is that lidocaine block during parturition is safe to the
fetus [145,146]. In the Collaborative Perinatal Project, lidocaine was generally
not associated with fetal malformations among 293 infants who were exposed in
utero during the first trimester [59]. Lidocaine is classified as a risk factor B
during pregnancy [85]. Intravenous lidocaine has been administered to mothers
with ventricular arrhythmias with good fetal outcomes [147]. Although the
teratogenic potential of oral lidocaine is small, topical application is often unnec-
essary for endoscopy during pregnancy. The pregnant patient who is administered
topical lidocaine should be instructed to gargle and spit out, rather than swallow,
the preparation to minimize systemic absorption. Lidocaine should be adminis-
tered intravenously only at low dose when deemed necessary by an anesthesi-
ologist for endoscopy.

Sedative and analgesic medications administered by anesthesiologists

Propofol (category B)

Anesthesiologists increasingly use propofol, a short-acting parenteral anes-

thetic, for endoscopy, but gastroenterologists have traditionally avoided using
propofol because of a narrow therapeutic index, potential respiratory depression,
and legal restrictions in certain states [83]. A large study has reported no
significant risks from nurse-administered propofol during endoscopy under
the supervision of an attending gastroenterologist [148]. Potential advantages
of propofol over conventional endoscopic anesthetics include a shorter time of
onset, greater depth of sedation, shorter recovery time, and earlier patient
discharge [149].
Administration of six times the maximal recommended human equivalent dose
in pregnant rats or rabbits revealed no teratogenicity [85]. Administration of
moderately high doses of propofol to pregnant sheep did not adversely affect
maternal uterine blood flow, maternal or fetal arterial pressure and heart rate, fetal
18 cappell

heart rate variability, or pregnancy outcome [150]. Propofol rapidly transfers

across the placenta near term in humans [151,152]. In one study, 20 infants who
were exposed to propofol during parturition had depressed Apgar scores and
transient neurologic depression at birth compared with unexposed controls, but
the neurologic depression rapidly reversed postpartum [153]. In contrast,
numerous other studies that involved hundreds of patients reported no neonatal
toxicity from propofol administered during parturition [58,154–158]. However,
most studies agree that very high doses of propofol administered during
parturition may transiently depress neonatal neurobehavioral function [159].
Propofol is rated a risk factor B and is considered relatively safe during preg-
nancy, but the safety of first trimester exposure has been inadequately studied

Ketamine (category B)

Anesthesiologists sometimes use ketamine for endoscopy because of its rapid

action of onset and short duration of effects [160], particularly in patients who are
expected to experience insufficient sedation from propofol. Multiple studies have
demonstrated no teratogenic effects in rats, mice, rabbits, and dogs that were
administered high doses during organogenesis or near delivery [161]. Exposure
of five pregnant monkeys to ketamine during pregnancy resulted in no untoward
fetal effects, but high dose exposure during delivery resulted in profound,
but transitory, neonatal respiratory depression [162]. Exceedingly high dose
administration of ketamine to neonatal mice can cause degeneration of neurons,
loss of cerebral cortex, and decreased learning ability in maze trials in adult-
hood [163].
Ketamine rapidly crosses the placenta to the fetus in humans [164]. It is
commonly used clinically for intrapartum anesthesia. Ketamine administration
during delivery occasionally causes maternal dysphoria [62]. Ketamine has
oxytocic effects, causes an increased basal uterine tone as well as increased
frequency and amplitude of uterine contractions [165], and can increase the blood
pressure in the mother [166]. Both the uterine and blood pressure effects are
transient, short lasting, and dose-dependent. Maternal ketamine administration
just before delivery does not adversely affect neonatal blood pressure [165,167].
Ketamine administration during delivery can cause transient neonatal
depression, reflected in lower initial Apgar scores and the need for neonatal
resuscitation [168]. This phenomenon is most evident with high dose admin-
istration and prolonged induction-to-delivery times [168]. The neurobehavioral
depression may last for up to 2 days after delivery [169]. Maternal ketamine
administration during labor, however, appears to cause less neonatal respiratory
depression than other sedatives [62]. High doses of ketamine administered to the
mother during delivery can transiently increase neonatal muscle tone [170].
Ketamine has not been associated with teratogenicity [171]. However, ketamine
administered during the first trimester has not apparently been reported. Ketamine
is rated as a class B drug during pregnancy, but carries the caveats that fetal safety
sedation and analgesia during pregnancy 19

during organogenesis is unstudied in humans, and extremely high or prolonged

administration during pregnancy might be unsafe.

Sedative and analgesic reversal agents

Naloxone (category B)

Naloxone, a rapidly acting opiate antagonist, is sometimes administered after

endoscopy to reverse the effects of narcotics that were administered during
endoscopy. It does not produce narcotic effects or respiratory depression at
clinically used dosages [172]. It rapidly crosses the placenta, and appears in fetal
plasma within 2 minutes of intravenous maternal injection [58,173]. Fetal serum
levels peak at about one-half of maternal levels after maternal intravenous
injection [173]. Naloxone administered at up to 50 times the maximal equivalent
human dose in pregnant mice and rats was not fetotoxic, but rat pups that were
exposed to naloxone during lactation developed long-lasting hyperalgesia
Naloxone administration has been analyzed during the third trimester.
Intravenous infusion of 0.4 mg of naloxone in 27 healthy pregnant women at
37 to 39 weeks of gestation led to an increase in fetal gross movements,
respiratory movements, and heart rate acceleration, without subsequent neonatal
toxicity [175]. Infant neurobehavioral scores were similar after their mothers had
received meperidine alone or meperidine plus naloxone during labor [169,176].
Naloxone was safely administered to newborns immediately postpartum to
reverse narcotic depression, including depressed respiration or, somnolence that
followed administration of narcotics to the mother during labor [177,178].
In one study, eight otherwise normal fetuses with decreased heartbeat vari-
ability intrapartum, were administered naloxone to increase the heartbeat
variability based on the theory that elevated fetal endorphin levels depress the
normal fetal heart rate and depress the normal fetal heartbeat variability. One of
the infants developed fatal respiratory failure and convulsions soon after the drug
was administered [179].
Naloxone administration is contraindicated for pregnant patients who are
dependent on opiates. Naloxone administration can precipitate the opiate
withdrawal syndrome in the mother and can precipitate a similar withdrawal syn-
drome in the neonate because of transplacental opiate transfer. Neonatal symptoms
include restlessness, anxiety, insomnia, irritability, hyperalgesia, nausea, and
muscle cramps [63,180]. One newborn, whose mother was opioid-dependent,
suffered convulsions that were precipitated by naloxone administration [181].
Naloxone is rated a category B drug during pregnancy [85]. Naloxone is not
recommended for routine use after endoscopy during pregnancy because of one
reported fatality associated with neonatal administration. Patients should be
monitored in a recovery unit with intravenous access and electrocardiographic
monitoring until they recover from narcotic-induced drowsiness. Naloxone
20 cappell

administration should be restricted to pregnant patients who suffer signs of

potential narcotic toxicity, such as respiratory depression, systemic hypotension,
or unresponsiveness, and should be administered, in these cases, in small graded
doses that are titrated to the desired effect. Naloxone overdose should be avoided.
It can cause maternal myocardial infarction, pulmonary edema, or severe hyper-
tension [62].

Flumazenil (category C)

Flumazenil rapidly reverses the central effects of benzodiazepines [182]. It is

used after endoscopy to reverse the effects of oversedation with benzodiazepines
that were administered during endoscopy [183]. The administration of flumazenil
to pregnant rats and rabbits during or after organogenesis at several hundred
times the maximal recommended human dose revealed no teratogenicity [85].
Flumazenil was not embryocidal when administered at 60 times the recom-
mended human dose in pregnant rabbits, but was embryocidal at 200 times the
recommended human dose [85]. Prolonged, high-dose administration to pregnant
rats in late gestation may result in subtle neurobehavioral changes in their male
offspring [184].
Little is known about flumazenil safety during pregnancy in humans. Drug
transfer across the human placenta to the fetus is unstudied. Transplacental
transfer is theoretically likely because of the low molecular weight of the
compound, but this transfer is likely to be small from a single drug bolus because
of the short drug half-life. One somnolent pregnant patient at 36 weeks of
gestation developed fetal cardiotocographic abnormalities of a decreased basal
fetal heart rate, decreased beat-to-beat cardiac variability, and absent cardiac
accelerations after a diazepam overdose. The patient rapidly awoke and the fetal
cardiotocographic abnormalities rapidly reversed after intravenous flumazenil
administration [185]. The mother delivered a healthy infant 2 weeks later. In
another case report, a healthy infant was born after in utero exposure to
flumazenil just before cesarean section [186]. In a third case, administration of
flumazenil in the third trimester was not associated with fetal toxicity [187].
Little is also known about flumazenil toxicity in neonates. Flumazenil was
successfully used to reverse recurrent apnea in two newborn infants whose
mothers had taken high doses of diazepam during late pregnancy [188,189].
Intravenous flumazenil was also successfully used to reverse unresponsiveness
and hypotonicity in a 4-month-old infant after intravenous midazolam sedation
[190]. The infant subsequently did well.
Flumazenil is rated a category C drug during pregnancy [85]. Flumazenil
should be used only to reverse benzodiazepine overdose during pregnancy be-
cause the fetal risks are unknown [85]. For this indication, the known maternal
benefits should greatly outweigh the unknown, but unlikely, fetal risks.
Flumazenil overdose can cause maternal seizures, particularly when administered
to patients who are chronically habituated to benzodiazepines [191]. This
sedation and analgesia during pregnancy 21

overdose can be prevented by careful and slow titration and the administration of
the minimal dosage of benzodiazepines required for endoscopy [83].

Future trends: anesthesiologic monitoring

Automated electroencephalogram monitors that use the bispectral (BIS) index

(Aspect Medical Systems, Natick, Massachusetts) or Narcotrend (Monitor
Technik, Germany), are being tested to quantitatively define the level of anes-
thesia [192–194]. This technology might reduce anesthesia requirements for
endoscopy during pregnancy and thereby decrease fetotoxicity. The fetus is
routinely monitored during surgery in the third trimester to rapidly detect fetal
distress. Fetal monitoring may, likewise, improve fetal safety during endoscopy,
particularly for therapeutic ERCP [5].

Alternatives to conventional endoscopy

Alternatives to gastrointestinal endoscopy, including an upper gastrointestinal

series, barium enema, abdominal roentgenogram, mesenteric angiogram,
computerized tomography, and virtual colonoscopy, are useful in the general
population and are theoretically desirable for preganant patients because they
require minimal or no anesthesiologic medications. But these tests are generally
contraindicated because of radiation teratogenicity [12]. Likewise, bleeding scans
are relatively contraindicated during pregnancy because of the fetal risks from
ionizing radiation.
Ultranarrow upper gastrointestinal endoscopes may permit gastrointestinal
intubation with minimal anesthesia and with reduced mechanical pressure on the
uterus [195]. These benefits are especially attractive during pregnancy to
minimize exposure to potentially teratogenic anesthetic medications and to avoid
endoscopic trauma to the uterus. These endoscopes have not been studied dur-
ing pregnancy.
Videocapsule endoscopy is currently used to examine the small bowel beyond
the ligament of Treitz, because this area is relatively inaccessible to conventional
tube endoscopy [196]. Videocapsule endoscopy has theoretical advantages during
pregnancy: the examination does not require sedation and does not cause
mechanical pressure on the uterus. The safety of videocapsule endoscopy during
pregnancy is currently unstudied and unknown. Intestinal compression by the
enlarged gravid uterus might theoretically retard videocapsule progression, but
this may not be a significant practical problem. Technical innovations could
render videocapsule endoscopy a viable alternative to EGD or colonoscopy dur-
ing pregnancy. In string videocapsule endoscopy of the esophagus, a string is
attached to the videocapsule for retrieval of the videocapsule after esophageal
passage and esophageal videophotography [197]. This test has the theoretical
22 cappell

advantages during pregnancy of minimal test invasiveness and lack of need for
anesthesia, but test safety has not been evaluated during pregnancy.
Fecal or serologic molecular markers are being used experimentally to detect
early colon cancer. In a preliminary study, a multitarget molecular assay for
mutations in the p53 and APC genes, microsatellite instability, and other mo-
lecular markers had a sensitivity of 91% and a specificity of 100% for colon
cancer [198]. Recent studies have demonstrated a much lower test sensitivity
(only 18.2%) and specificity for detection of advanced colonic adenomatous
polyps [199]. Such a test could be used to screen for suspected colon cancer to
limit colonoscopy during pregnancy to patients who have a positive result on the
screening test, provided that the test sensitivity is improved by adding more
markers to the test array.
Although virtual colonoscopy that uses computerized tomography has no
foreseeable role in pregnancy because of radiation teratogenicity [200], virtual
colonoscopy that uses magnetic resonance imaging (MRI) would theoretically
be attractive during pregnancy because MRI is apparently much safer than
radiation during pregnancy. In MRI, multifrequency pulses are applied in the
presence of a magnetic field gradient to excite hydrogen ions. MRI without
contrast has no known harmful effects in nonpregnant humans, except in patients
with metallic foreign bodies or with implanted electronic devices, such as cardiac
pacemakers [201].
Magnetic resonance cholangiopancreatography (MRCP) is increasingly
supplanting diagnostic ERCP in the general population [202]. MRCP is a par-
ticularly attractive alternative to diagnostic ERCP during pregnancy because it
avoids radiation teratogenicity and does not require sedation and analgesia [203].
MRI is being used increasingly to evaluate the abdomen and retroperitoneum
during pregnancy. Short-term exposure to electromagnetic radiation from MRI
does not produce harmful fetal effects [204,205].


Endoscopy during pregnancy raises the unique issue of fetal safety. Endo-
scopic medications comprise a significant component of fetal endoscopic risks.
Before endoscopy, the gastroenterologist or anesthesiologist should evaluate the
potential fetal risks of sedation and analgesia, identify any contraindications to
endoscopy, stabilize the maternal medical status as necessary, and correct
maternal hypoxia or hypotension. The mother should be informed about the
potential teratogenic risks of endoscopic medications during pregnancy, espe-
cially during organogenesis during the first trimester. Patients who receive
sedation and analgesia should be monitored during endoscopy by continuous
electrocardiography, continuous pulse oximetry, and intermittent sphygmoma-
nometry, as well as by the pulse and respiratory rate. General principles of seda-
tion and analgesia during pregnancy include use of the minimal effective dose,
avoidance of unnecessary medications, and preferable use of FDA category B
sedation and analgesia during pregnancy 23

medications. Medications used for sedation and analgesia during pregnancy

include meperidine (category B), fentanyl (category C), midazolam (category D),
lidocaine (category B), propofol (category B), and ketamine (category B).
Endoscopy can be performed with sedation and analgesia during pregnancy, with
appropriate precautions, for strong endoscopic indications.


[1] Arrowsmith JB, Gerstman BB, Fleischer DE, et al. Results from the American Society for
Gastrointestinal Endoscopy/US Food and Drug Administration collaborative study on com-
plication rates and drug use during gastrointestinal endoscopy. Gastrointest Endosc 1991;
37:421 – 7.
[2] Cooper GS. Indications and contraindications for upper gastrointestinal endoscopy. Gastrointest
Endosc Clin N Am 1994;4:439 – 54.
[3] Newcomer MK, Brazer SR. Complications of upper gastrointestinal endoscopy and their
management. Gastrointest Endosc Clin N Am 1994;4:551 – 70.
[4] Cappell MS, Sidhom O, Colon V. A study at ten medical centers of the safety and efficacy of
48 flexible sigmoidoscopies and 8 colonoscopies during pregnancy with follow-up of
fetal outcome and with comparison to control groups. Dig Dis Sci 1996;41:2353 – 60.
[5] Cappell MS, Colon V, Sidhom OA. A study of eight medical centers of the safety and clinical
efficacy of esophagogastroduodenoscopy in 83 pregnant females with follow-up of fetal
outcome and with comparison to control groups. Am J Gastroenterol 1996;91:348 – 54.
[6] Cappell MS, Sidhom O. Multicenter, multiyear study of safety and efficacy of flexible
sigmoidoscopy during pregnancy in 24 females with follow-up of fetal outcome. Dig Dis Sci
1995;40:256 – 62.
[7] Cappell MS, Sidhom O. A multicenter, multiyear study of the safety and clinical utility of
esophagogastroduodenoscopy in 20 consecutive pregnant females with follow-up of fetal
outcome. Am J Gastroenterol 1993;88:1900 – 5.
[8] Castro LP. Reflux esophagitis as the cause of heartburn in pregnancy. Am J Obstet Gynecol
1967;98:1 – 10.
[9] Jamidar PA, Beck GJ, Hoffman BJ, et al. Endoscopic retrograde cholangiopancreatography
in pregnancy. Am J Gastroenterol 1995;90:1263 – 7.
[10] Cappell MS. Gastrointestinal endoscopy in pregnant women: risks versus benefits. Nature
Clinical Practice Gastroenterology & Hepatology 2005;2:376 – 7.
[11] Cappell MS. The safety and efficacy of gastrointestinal endoscopy during pregnancy.
Gastroenterol Clin North Am 1998;27(1):37 – 71.
[12] Cappell MS. The fetal safety and clinical efficacy of gastrointestinal endoscopy during preg-
nancy. Gastroenterol Clin North Am 2003;32(1):123 – 79.
[13] Frank B. Endoscopy in pregnancy. In: Karlstadt RG, Surawicz CM, Croitoru R, editors.
Gastrointestinal disorders during pregnancy. Arlington (VA)7 American College of Gastro-
enterology; 1994. p. 24 – 9.
[14] Epstein H, Waxman A, Gleicher N, et al. Meperidine-induced sinusoidal fetal heart rate pat-
tern and reversal with naloxone. Obstet Gynecol 1982;59(Suppl):22 – 5.
[15] Kim-Lo SH, Ciliberto CF, Smiley RM. Anesthesia: principles and techniques. In: Cohen WR,
editor. Cherry and Merkatz’s complications of pregnancy. 5th edition. Philadelphia7 Lippincott
Williams & Wilkins; 2000. p. 853 – 71.
[16] Rosenberg L, Mitchell AA, Parsells JL, et al. Lack of relation of oral clefts to diazepam use
during pregnancy. N Engl J Med 1983;309:1282 – 5.
[17] DiSario JA, Waring JP, Talbert G, et al. Monitoring of blood pressure and heart rate during
routine endoscopy: a prospective, randomized, controlled study. Am J Gastroenterol 1991;86:
956 – 60.
24 cappell

[18] Hampton KK, Grant PJ, Primrose J, et al. Haemostatic responses and vasopressin release during
colonoscopy in man. Clin Sci 1991;81:257 – 60.
[19] Lieberman DA, Wuerker CK, Katon RM. Cardiopulmonary risk of esophagogastroduodeno-
scopy. Gastroenterology 1985;88:468 – 72.
[20] Mathews PK, Ona FV, Damevski K, et al. Arrhythmias during upper gastrointestinal
endoscopy. Angiology 1979;30:834 – 40.
[21] Dark DS, Campbell DR, Wesselius U. Arterial oxygen desaturation during gastrointestinal
endoscopy. Am J Gastroenterol 1990;85:1317 – 21.
[22] Rozen F, Fireman Z, Gilat T. The causes of hypoxemia in elderly patients during endoscopy.
Gastrointest Endosc 1982;28:243 – 6.
[23] Gilbert DA, Silverstein FE, Tedesco FJ. National ASGE survey on upper gastrointestinal
bleeding: complications of endoscopy. Dig Dis Sci 1981;26(Suppl):55 – 9.
[24] Freeman JM, Freeman AD. Cerebral palsy and the dbad babyT malpractice crisis: New York
State shines light toward the end of the tunnel. Am J Dis Child 1992;146:725 – 7.
[25] Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphinc-
terotomy. N Engl J Med 1996;335:909 – 18.
[26] Andreoli M, Sayegh SK, Hoefer R, et al. Laparoscopic cholecystectomy for recurrent gallstone
pancreatitis during pregnancy. South Med J 1996;89:1114 – 5.
[27] Wishner JD, Zolfaghari D, Wohlgemuth SD, et al. Laparoscopic cholecystectomy in pregnancy:
a report of 6 cases and review of the literature. Surg Endosc 1996;10:314 – 8.
[28] Gyokeres T, Topa L, Marton I, et al. Endoscopic cystogastrostomy during pregnancy.
Gastrointest Endosc 2001;53:516 – 8.
[29] Ryan ME. Endoscopic management of a pancreatic pseudocyst during pregnancy. Gastrointest
Endosc 1992;38:605 – 8.
[30] Aggarwal N, Sawhney H, Vasishta K, et al. Non-cirrhotic portal hypertension in pregnancy.
Int J Gynecol Obstet 2001;72:1 – 7.
[31] Macedo C, Carvalho L, Ribeiro T. Endoscopic sclerotherapy for upper gastrointestinal bleeding
due to Mallory-Weiss syndrome [letter]. Am J Gastroenterol 1995;90:1364 – 5.
[32] Fiest TC, Foong A, Chokhavatia S. Successful balloon dilation of achalasia during pregnancy.
Gastrointest Endosc 1993;39:810 – 2.
[33] Farca A, Aguilar ME, Rodriguez G, et al. Biliary stents as temporary treatment for chole-
docholithiasis in pregnant patients. Gastrointest Endosc 1997;46:99 – 101.
[34] Koh ML, Lipkin EW. Nutrition support of a pregnant comatose patient via percutaneous
endoscopic gastrostomy. JPEN J Parenter Enteral Nutr 1993;17:384 – 7.
[35] Serrano P, Velloso A, Garcia-Luna PP, et al. Enteral nutrition by percutaneous endoscopic
gastrojejunostomy in severe hyperemesis gravidarum: a report of two cases. Clin Nutr 1998;
17:135 – 9.
[36] Cappell MS. Gastrointestinal endoscopy in high-risk patients. Dig Dis 1996;14:228 – 44.
[37] Kammerer WS. Nonobstetric surgery during pregnancy. Med Clin North Am 1979;63:
1157 – 64.
[38] Brent RL. The effect of embryonic and fetal exposure to x-ray, microwaves, and ultra-
sound: counseling the pregnant and nonpregnant patient about these risks. Semin Oncol 1989;
16:347 – 68.
[39] Steinlauf AF, Traube M. Gastrointestinal complications. In: Burrow GN, Duffy TP, editors.
Medical complications during pregnancy. 5th edition. Philadelphia7 WB Saunders; 1999.
p. 255 – 68.
[40] Tamir IL, Bomghard FS, Klein SR. Acute appendicitis in the pregnant patient. Am J Surg
1990;160:571 – 6.
[41] Cappell MS, Friedel D. Abdominal pain during pregnancy. Gastroenterol Clin N Am 2003;
32:1 – 58.
[42] Baer JL, Reis RA, Arens RA. Appendicitis in pregnancy with changes in position and axis of
the normal appendix in pregnancy. JAMA 1932;98:1359 – 64.
[43] Esposito TJ, Gens DR, Smith LG, et al. Trauma during pregnancy: a review of 79 cases.
Arch Surg 1991;126:1073 – 8.
sedation and analgesia during pregnancy 25

[44] Schwartz WJ, Thurnau CR. Iron deficiency anemia in pregnancy. Clin Obstet Gynecol
1995;38:443 – 54.
[45] Pritchard JA. Change in the blood volume during pregnancy and delivery. Anesthesiology
1965;26:393 – 9.
[46] Martin C, Varner MW. Physiologic changes in pregnancy: surgical implications. Clin Obstet
Gynecol 1994;37:241 – 55.
[47] Depue RH, Bernstein L, Ross RK, et al. Hyperemesis gravidarum in relation to estradiol levels,
pregnancy outcome, and other maternal factors: a seroepidemiologic study. Am J Obstet
Gynecol 1987;156:1137 – 41.
[48] Eichenberg BJ, Vanderlinden J, Miguel L, et al. Laparoscopic cholecystectomy in the third
trimester of pregnancy. Am Surg 1996;62:874 – 7.
[49] Kort B, Katz VL, Watson WJ. The effect of nonobstetric operation during pregnancy. Surg
Gynecol Obstet 1994;177:371 – 6.
[50] Berg JC, Miller R, Burkhalter E. Clinical value of pulse oximetry during routine diagnostic
and therapeutic endoscopic procedures. Endoscopy 1991;23:328 – 30.
[51] Gianopoulos JG. Establishing the criteria for anesthesia and other precautions for surgery
during pregnancy. Surg Clin North Am 1995;75:33 – 45.
[52] Katz JD, Hook R, Barash PG. Fetal heart rate monitoring in pregnant patients undergoing
surgery. Am J Obstet Gynecol 1996;125:267 – 9.
[53] Gardner-Medwin JM, Powell RJ. Thalidomide: the way forward. Postgrad Med J 1994;
70:860 – 2.
[54] Newman LM, Johnson EM, Staples RE. Assessment of the effectiveness of animal de-
velopmental toxicity testing for human safety. Reprod Toxicol 1993;7:359 – 90.
[55] US Department of Health and Human Services. Vital statistics of the United States 1989: Vol I.
Natality. Hyattsville (MD)7 National Center for Health Statistics; 1993.
[56] US Bureau of the Census. Statistical abstract of the United States 1993: the national data book.
113th edition. Washington7 US Bureau of the Census; 1993.
[57] Jefferies JA, Robboy SJ, O’Brien PC, et al. Structural anomalies of the cervix and vagina in
women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project. Am J Obstet Gynecol
1984;148:59 – 66.
[58] Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to
fetal and neonatal risk. 7th edition. Philadelphia7 Lippincott, Williams & Wilkins; 2005.
[59] Heinonen OP, Stone D, Shapiro S. Birth defects and drugs in pregnancy. Boston7
John Wright; 1982.
[60] Szeto HH, Zervoudakis IA, Cederquist LL, et al. Amniotic fluid transfer of meperidine
from maternal plasma in early pregnancy. Obstet Gynecol 1978;52:59 – 62.
[61] Savona-Ventura C, Sammut M, Sammut C. Pethidine blood concentrations at time of birth.
Int J Gynaecol Obstet 1991;36:103 – 7.
[62] Hawkins JL. Obstetric anesthesia and analgesia. In: Scott JR, Gibbs RS, Karlan BY, et al,
editors. Danforth’s obstetrics and gynecology. 9th edition. Philadelphia7 Lippincott Williams &
Wilkins; 2003. p. 57 – 73.
[63] Kopecky EA, Koren G. Maternal drug abuse: effects on the fetus and neonate. In: Polin RA,
Fox WW, Abman SH, editors. Fetal and neonatal physiology. 3rd edition. Philadelphia7
Saunders; 2004. p. 234 – 49.
[64] Fairlie FM, Marshall L, Walker JJ, et al. Intramuscular opioids for maternal pain relief in
labour: a randomized controlled trial comparing pethidine with diamorphine. Br J Obstet
Gynaecol 1999;106:1181 – 7.
[65] Olofsson C, Ekblom A, Ekman-Ordeberg G, et al. Lack of analgesic effect of systemically
administered morphine or pethidine on labour pain. Br J Obstet Gynaecol 1996;103:968 – 72.
[66] Sheikh A, Tunstall ME. Comparative study of meptazinol and pethidine for the relief of pain
in labour. Br J Obstet Gynaecol 1986;93:264 – 9.
[67] Belfrage P, Boreus LO, Hartvig P, et al. Neonatal depression after obstetrical analgesia with
pethidine: the role of injection-delivery time interval and the plasma concentrations of
pethidine and norpethidine. Acta Obstet Gynecol Scand 1981;60:43 – 9.
26 cappell

[68] Mattingly JE, D’Alessio J, Ramanathan J. Effects of obstetric analgesics and anesthetics on
the neonate: a review. Paediatr Drugs 2003;5:615 – 27.
[69] Belsey EM, Rosenblatt DB, Lieberman BA, et al. The influence of maternal analgesia on
neonatal behavior. I. Pethidine. Br J Obstet Gynaecol 1981;88:398 – 406.
[70] Borgstedt AD, Rosen MG. Medication during labor correlated with behavior and EEG of
the newborn. Am J Dis Child 1968;115:21 – 4.
[71] Hodgkinson R, Bhatt M, Grewal G, et al. Neonatal neurobehavior in the first 48 hours
of life: effect of the administration of meperidine with and without naloxone in the mother.
Pediatrics 1978;62:294 – 8.
[72] Hodgkinson R, Bhatt M, Wang CN. Double-blind comparison of the neurobehaviour
of neonates following the administration of different doses of meperidine to the mother.
Can Anaesth Soc J 1978;25:405 – 11.
[73] Kulmert BR, Lirm PL, Kennard MJ, et al. Effects of low doses of meperidine on neonatal
behavior. Anesth Analg 1985;64:335 – 42.
[74] Nissen E, Lilja G, Matthiesen AS, et al. Effects of maternal pethidine on infants’ developing
breast feeding behaviour. Acta Paediatr 1995;84:140 – 5.
[75] Hodgkinson R, Husain FJ. The duration of effect of maternally administered meperidine on
neonatal neurobehavior. Anesthesiology 1982;56:51 – 2.
[76] Buck C. Drugs in pregnancy [letter]. Can Med Assoc J 1975;112:1285.
[77] Buck C, Gregg R, Stavraky K, et al. The effect of single prenatal and natal complications
upon the development of children of mature birth weight. Pediatrics 1969;43:942 – 5.
[78] Golding J, Greenwood R, Birmingham K, et al. Childhood cancer, intramuscular vitamin K,
and pethidine given during labour. BMJ 1992;305:341 – 6.
[79] Barrett JM, Boehm FH. Fetal heart rate responses to meperidine alone and in combination
with propiomazine. South Med J 1983;76:1480 – 3.
[80] Petrie RH. Influence of meperidine on fetal movements and heart rate beat-to-beat variability
in the active phase of labor. Am J Perinatol 1988;5:306.
[81] Cunningham FG, Gant NF, Leveno KJ, et al. Analgesia and sedation. In: Williams Obstetrics.
21st edition. New York7 McGraw-Hill; 2001. p. 537 – 63.
[82] Sosa CG, Balaguer E, Alonso JG, et al. Meperidine for dystocia during the first stage of labor:
A randomized controlled trial. Am J Obstet Gynecol 2004;191:1212 – 8.
[83] Freeman ML. Sedation and monitoring for gastrointestinal endoscopy. In: Yamada T, Alpers DH,
Kaplowitz N, et al, editors. Textbook of gastroenterology. 4th edition. Philadelphia7 Lippincott
Williams & Wilkins; 2003. p. 2812 – 24.
[84] Martin LV, Jurand A. The absence of teratogenic effects of some analgesics used in anaesthesia:
additional evidence from a mouse model. Anaesthesia 1992;47:473 – 6.
[85] Anonymous. Physician’s desk reference. 59th edition. Montvale (NJ)7 Thomson Healthcare;
[86] Cooper J, Jauniaux E, Gulbis B, et al. Placental transfer of fentanyl in early human pregnancy
and its detection in fetal brain. Br J Anaesth 1999;82:929 – 31.
[87] Shannon C, Jauniaux E, Gulbis B, et al. Placental transfer of fentanyl in early human preg-
nancy. Hum Reprod 1998;13:2317 – 20.
[88] Fernando R, Bonello E, Gill P, et al. Neonatal welfare and placental transfer of fentanyl and
bupivacaine during ambulatory combined spinal epidural analgesia for labour. Anaesthesia
1997;52:517 – 24.
[89] Morley-Forster PK, Reid DW, Vandeberghe H. A comparison of patient-controlled analgesia
fentanyl and alfentanil for labour analgesia. Can J Anaesth 2000;47:113 – 9.
[90] Nelson KE, Rauch T, Terebuh V, et al. A comparison of intrathecal fentanyl and sufentanil for
labor analgesia. Anesthesiology 2002;96:1070 – 3.
[91] Rayburn W, Rathke A, Leuschen MP, et al. Fentanyl citrate analgesia during labor. Am J Obstet
Gynecol 1989;161:202 – 6.
[92] Pace MC, Aurilio C, Bulletti C, et al. Subarachnoid analgesia in advanced labor: a comparison
of subarachnoid analgesia and pudendal block in advanced labor: analgesic quality and obstet-
ric outcome. Ann N Y Acad Sci 2004;1034:356 – 63.
sedation and analgesia during pregnancy 27

[93] Porter J, Bonello E, Reynolds F. Effect of epidural fentanyl on neonatal respiration. Anes-
thesiology 1998;89:79 – 85.
[94] Carrie LE, O’Sullivan GM, Seegobin R. Epidural fentanyl in labour. Anaesthesia 1981;36:
965 – 9.
[95] Lindemann R. Respiratory muscle rigidity in a preterm infant after use of fentanyl during
caesarean section. Eur J Pediatr 1998;157:1012 – 3.
[96] Regan J, Chambers F, Gorman W, et al. Neonatal abstinence syndrome due to prolonged
administration of fentanyl in pregnancy. Br J Obstet Gynaecol 2000;107:570 – 2.
[97] Bakke OM, Haram K. Time-course of transplacental passage of diazepam: influence of
injection-delivery interval on neonatal drug concentrations. Clin Pharmacokinet 1982;7:
353 – 62.
[98] Jauniaux E, Jurkovic D, Lees C, et al. In-vivo study of diazepam transfer across the first
trimester human placenta. Hum Reprod 1996;11:889 – 92.
[99] Kanto J, Sjovall S, Erkkola R, et al. Placental transfer and maternal midazolam kinetics. Clin
Pharmacol Ther 1983;33:786 – 91.
[100] Shepard TH. Catalog of teratogenic agents. 6th edition. Baltimore7 Johns Hopkins University
Press; 1989. p. 203 – 6.
[101] Saxen I. Associations between oral clefts and drugs taken during pregnancy. Int J Epidemiol
1975;4:37 – 44.
[102] Saxen I. Epidemiology of cleft lip and palate: an attempt to rule out chance correlations. Br J
Prev Soc Med 1975;29:103 – 10.
[103] Saxen I, Saxen L. Association between maternal intake of diazepam and oral clefts. Lancet
[104] Rivas F, Hernandez A, Cantu JM. Acentric craniofacial cleft in a newborn female prenatally
exposed to a high dose of diazepam. Teratology 1984;30:179 – 80.
[105] Safra MJ, Oakley Jr GP. Association between cleft lip with or without cleft palate and prenatal
exposure to diazepam. Lancet 1975;2:478 – 80.
[106] Safra MJ, Oakley Jr GP. Valium: an oral cleft teratogen? Cleft Palate J 1976;13:198 – 200.
[107] Czeizel A. Diazepam, phenytoin, and etiology of cleft lip and/or cleft palate. Lancet 1976;
[108] Lakos P, Czeizel E. A teratological evaluation of anticonvulsant drugs. Acta Paediatr Acad Sci
Hung 1977;18:145 – 53.
[109] Shiono PH, Mills JL. Oral clefts and diazepam use during pregnancy. N Engl J Med 1984;
[110] Czeizel A. Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary. Reprod
Toxicol 1987–88;1:183 – 8.
[111] Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzodiazepine during fetal life.
Lancet 1992;340:694 – 6.
[112] McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod
Toxicol 1994;8:461 – 75.
[113] Yankowitz J. Teratology and drugs in pregnancy. In: Scott JR, Gibbs RS, Karlan BY, et al,
editors. Danforth’s obstetrics and gynecology. 9th edition. Philadelphia7 Lippincott Williams &
Wilkins; 2003. p. 129 – 41.
[114] Bracken MB, Holford TR. Exposure to prescribed drugs in pregnancy and association with
congenital malformations. Obstet Gynecol 1981;58:336 – 44.
[115] Rothman KJ, Fyler DC, Goldblatt A, et al. Exogenous hormones and other drug exposures
of children with congenital heart disease. Am J Epidemiol 1979;109:433 – 9.
[116] Courtens W, Vamos E, Hainaut M, et al. Mobius syndrome in an infant exposed in utero
to benzodiazepines. J Pediatr 1992;121:833 – 4.
[117] Ornoy A, Arnon J, Shechtman S, et al. Is benzodiazepine use during pregnancy really
teratogenic? Reprod Toxicol 1998;12:511 – 5.
[118] Dolovich LR, Addis A, Vaillancourt JMR, et al. Benzodiazepine use in pregnancy and major
malformations or oral cleft: meta-analysis of cohort and case-controlled studies. BMJ 1998;
317:839 – 43.
28 cappell

[119] Laegreid L, Olegard R, Wahlstrom J, et al. Abnormalities in children exposed to benzo-

diazepines in utero [letter]. Lancet 1987;1:108 – 9.
[120] Laegreid L, Olegard R, Wahlstrom J, et al. Teratogenic effects of benzodiazepine use during
pregnancy. J Pediatr 1989;114:126 – 31.
[121] Gillberg C. ‘‘Floppy infant syndrome’’ and maternal diazepam. Lancet 1977;2(8031):244.
[122] Haram K. ‘‘Floppy infant syndrome’’ and maternal diazepam. Lancet 1977;2(8038):612 – 3.
[123] Speight AN. Floppy-infant syndrome and maternal diazepam and/or nitrazepam [letter]. Lancet
[124] Backes CR, Cordero L. Withdrawal symptoms in the neonate from presumptive intra-uterine
exposure to diazepam: report of a case. J Am Osteopath Assoc 1980;79:584 – 5.
[125] Rementeria JL, Bhatt K. Withdrawal symptoms in neonates from intrauterine exposure to
diazepam. J Pediatr 1977;90:123 – 6.
[126] Einarson A, Selby P, Koren G. Abrupt discontinuation of psychotropic drugs during pregnancy:
fear of teratogenic risk and impact of counseling. J Psychiatry Neurosci 2001;26:44 – 8.
[127] Einarson A, Selby P, Koren G. Discontinuing antidepressants and benzodiazepines upon
becoming pregnant. Beware of the risks of abrupt discontinuation. Can Fam Physician 2001;47:
489 – 90.
[128] Macken E, Gevers AM, Hendrickx A, et al. Midazolam versus diazepam in lipid emulsion as
conscious sedation for colonoscopy with or without reversal of sedation with flumazenil.
Gastrointest Endosc 1998;47:57 – 61.
[129] Bach V, Carl P, Ravjo O, et al. A randomized comparison between midazolam and thiopental
for elective cesarean section anesthesia: III. Placental transfer and elimination in neonates.
Anesth Analg 1989;68:238 – 42.
[130] Kanto JH. Use of benzodiazepines during pregnancy, labour and lactation, with particular
reference to pharmacokinetic considerations. Drugs 1982;23:354 – 80.
[131] Bland BAR, Lawes EG, Duncan PW, et al. Comparison of midazolam and thiopental for rapid
sequence anesthetic induction for elective cesarean section. Anesth Analg 1987;66:1165 – 8.
[132] Crawford ME, Carl P, Bach V, et al. A randomized comparison between midazolam and
thiopental for elective cesarean section anesthesia. I. Mothers. Anesth Analg 1989;68:229 – 33.
[133] Ravlo O, Carl P, Crawford ME, et al. A randomized comparison between midazolam and
thiopental for elective cesarean section anesthesia. II. Neonates. Anesth Analg 1989;68:234 – 7.
[134] Wilson CM, Dundee JW, Moore J, et al. A comparison of the early pharmacokinetics of
midazolam in pregnant and nonpregnant women. Anaesthesia 1987;42:1057 – 62.
[135] Celleno D, Capogna G, Emanuelli M, et al. Which induction drug for cesarean section? A
comparison of thiopental sodium, propofol, and midazolam. J Clin Anesth 1993;5:284 – 8.
[136] Kanto J, Sjovall S, Erkkola R, et al. Placental transfer and maternal midazolam kinetics. Clin
Pharmacol Ther 1983;33:786 – 91.
[137] Tucker AP, Mezzatesta J, Nadeson R, et al. Intrathecal midazolam II: combination with
intrathecal fentanyl for labor pain. Anesth Analg 2004;98:1521 – 7.
[138] Padilla SL, Smith RD, Dugan K, et al. Laparascopically assisted gamete intrafallopian transfer
with local anesthesia and intravenous sedation. Fertil Steril 1996;66:404 – 7.
[139] Phillipson EH, Kuhnert BR, Syracuse CD. Maternal, fetal, and neonatal lidocaine levels
following local perineal infiltration. Am J Obstet Gynecol 1984;149:403 – 7.
[140] Scanlon JW, Brown Jr WU, Weiss JB, et al. Neurobehavioral responses of newborn infants after
maternal epidural anesthesia. Anesthesiology 1974;40:121 – 8.
[141] Abboud TK, David S, Costandi J, et al. Comparative maternal, fetal and neonatal effects
of lidocaine versus lidocaine with epinephrine in the parturient. Anesthesiology 1984;
[142] Shnider SM, Way EL. Plasma levels of lidocaine (Xylocaine) in mother and newborn following
obstetrical conduction anesthesia: clinical applications. Anesthesiology 1968;29:951 – 8.
[143] Liston WA, Adjepon-Yamoah KK, Scott DB. Foetal and maternal lignocaine levels after
paracervical block. Br J Anaesth 1973;45:750 – 4.
[144] Kim WY, Pomerance JJ, Miller AA. Lidocaine intoxication in a newborn following local
anesthesia for episiotomy. Pediatrics 1979;64:643 – 5.
sedation and analgesia during pregnancy 29

[145] Kileff ME, James III FM, Dewan DM, et al. Neonatal neurobehavioral responses after epi-
dural anesthesia for cesarean section using lidocaine and bupivacaine. Anesth Analg 1984;63:
413 – 7.
[146] Levy BT, Bergus GR, Hartz A, et al. Is paracervical block safe and effective? A prospec-
tive study of its association with neonatal umbilical artery pH values. J Fam Pract 1999;48:
778 – 84.
[147] Gowda RM, Khan IA, Mehta NJ, et al. Cardiac arrhythmias in pregnancy: clinical and
therapeutic considerations. Int J Cardiol 2003;88:129 – 33.
[148] Rex DK. The science and politics of propofol. Am J Gastroenterol 2004;99:2080 – 3.
[149] Lazzaroni M, Porro GB. Preparation, premedication, and surveillance. Endoscopy
2005;37:101 – 9.
[150] Alon E, Ball RH, Gillie MH, et al. Effects of propofol and thiopental on maternal and fetal
cardiovascular and acid-base variables in the pregnant ewe. Anesthesiology 1993;78:562 – 76.
[151] Dailland P, Cockshott ID, Lirzin JD, et al. Intravenous propofol during cesarean section:
placental transfer, concentrations in breast milk, and neonatal effects—a preliminary study.
Anesthesiology 1989;71:827 – 34.
[152] Sanchez-Alcaraz A, Quintana MB, Laguarda M. Placental transfer and neonatal effects of
propofol in caesarean section. J Clin Pharm Ther 1998;23:19 – 23.
[153] Celleno D, Capogna G, Tomassetti M, et al. Neurobehavioral effects of propofol on the neonate
following elective caesarean section. Br J Anaesth 1989;62:649 – 54.
[154] Abboud TK, Zhu J, Richardson M, et al. Intravenous propofol vs thiamylal-isoflurane for
caesarean section: comparative maternal and neonatal effects. Acta Anaesthesiol Scand 1995;
39:205 – 9.
[155] Cheng YJ, Wang YP, Fan SZ, et al. Intravenous infusion of low dose propofol for conscious
sedation in cesarean section before spinal anesthesia. Acta Anaesthesiol Sin 1997;35:79 – 84.
[156] Gregory MA, Gin T, Yau G, et al. Propofol infusion anaesthesia for caesarean section. Can J
Anaesth 1990;37:514 – 20.
[157] Gin T, O’Meara ME, Kan AF, et al. Plasma catecholamines and neonatal condition after
induction of anaesthesia with propofol or thiopentone at caesarean section. Br J Anaesth
1993;70:311 – 6.
[158] Gin T. Propofol during pregnancy. Acta Anaesthesiol Sin 1994;32:127 – 32.
[159] Yau G, Gin T, Ewart MC, et al. Propofol for induction and maintenance of anaesthesia
at caesarean section: a comparison with thiopentone/enflurane. Anaesthesia 1991;46:20 – 3.
[160] Gilger MA, Spearman RS, Dietrich CL, et al. Safety and effectiveness of ketamine as a sedative
agent for pediatric GI endoscopy. Gastrointest Endosc 2004;59:659 – 63.
[161] El-Karum AHA, Benny R. Embryotoxic and teratogenic action of ketamine. Ain Shams Med J
1976;27:459 – 63.
[162] Eng M, Bonica JJ, Akamatsu TJ, et al. Respiratory depression in newborn monkeys at
caesarean section following ketamine administration. Br J Anaesth 1975;47:917 – 21.
[163] Fredriksson A, Archer T, Alm H, et al. Neurofunctional deficits and potentiated apoptosis by
neonatal NMDA antagonist administration. Behav Brain Res 2004;153:367 – 76.
[164] Nishijima M. Ketamine in obstetric anesthesia: special reference to placental transfer and its
concentration in blood plasma. Acta Obstet Gynaecol Jpn 1972;19:80 – 93.
[165] Marx GF, Hwang HS, Chandra P. Postpartum uterine pressures with different doses of
ketamine. Anesthesiology 1979;50:163 – 6.
[166] Maduska AL, Hajghassemali M. Arterial blood gases in mothers and infants during ketamine
anesthesia for vaginal delivery. Anesth Analg 1978;57:121 – 3.
[167] Marx GF, Cabe CM, Kim YI, et al. Neonatal blood pressures. Anaesthesist 1976;25:318 – 22.
[168] Baraka A, Louis F, Dalleh R. Maternal awareness and neonatal outcome after ketamine
induction of anaesthesia for caesarean section. Can J Anaesth 1990;37:641 – 4.
[169] Hodgkinson R, Bhatt M, Kim SS, et al. Neonatal neurobehavioral tests following cesarean
section under general and spinal anesthesia. Am J Obstet Gynecol 1978;132:670 – 4.
[170] Corssen G. Ketamine in obstetric anesthesia. Clin Obstet Gynecol 1974;17:249 – 58.
[171] Friedman JM. Teratogen update: anesthetic agents. Teratology 1988;37:69 – 77.
30 cappell

[172] Fukuda K. Intravenous opioid anesthetics. In: Miller RD, editor. Miller’s anesthesia. 6th edition.
Philadelphia7 Churchill Livingstone; 2005. p. 379 – 437.
[173] Hibbard BM, Rosen M, Davies D. Placental transfer of naloxone. Br J Anaesth 1986;58:45 – 8.
[174] De-Castro RM, Cabral-Filho JE, Costa JA, et al. Neonatal treatment with naloxone causes
permanent hyperalgesia in rats. Braz J Med Biol Res 1993;27:747 – 51.
[175] Arduini D, Rizzo G, Dell’Acqua S, et al. Effect of naloxone on fetal behavior near term. Am J
Obstet Gynecol 1987;156:474 – 8.
[176] Brookshire GL, Shnider SM, Abboud TK, et al. Effects of naloxone on the mother and neonate
after intrathecal morphine for labor analgesia [abstract]. Anesthesiology 1983;59:A417.
[177] Bonta BW, Gagliardi JV, Williams V, et al. Naloxone reversal of mild neurobehav-
ioral depression in normal newborn infants after routine obstetric analgesia. J Pediatr
1979;94:102 – 5.
[178] Welles B, Belfrage P, de Chateau P. Effects of naloxone on newborn infant behavior after
maternal analgesia with pethidine during labor. Acta Obstet Gynecol Scand 1984;63:617 – 9.
[179] Goodlin RC. Naloxone and its possible relationship to fetal endorphin levels and fetal distress.
Am J Obstet Gynecol 1981;139:16 – 9.
[180] American Academy of Pediatrics Committee on Drugs. Neonatal drug withdrawal. Pediatrics
1998;101:1079 – 88.
[181] Gibbs J, Newson T, Williams J, et al. Naloxone hazard in infant of opioid abuser. Lancet 1989;
2:159 – 60.
[182] Hoffman EJ, Warren EW. Flumazenil: a benzodiazepine antagonist. Clin Pharm 1993;12:
641 – 56.
[183] Dunk AA, Norton AC, Hudson M, et al. The value of flumazenil in the reversal of midazolam-
induced sedation for upper gastrointestinal endoscopy. Aliment Pharmacol Ther 1990;4:35 – 42.
[184] Cagiano R, de Salvia MA, Giustino A, et al. Behavioral changes produced in rats by devel-
opmental exposure to flumazenil, a benzodiazepine receptor antagonist. Prog Neuropsycho-
pharmacol Biol Psychiatry 1993;17:151 – 9.
[185] Stahl MMS, Saldeen P, Vinge E. Reversal of fetal benzodiazepine intoxication using
flumazenil. Br J Obstet Gynaecol 1993;100:185 – 8.
[186] Shibata T, Kubota N, Yokoyama H. A pregnant woman with convulsion treated with diazepam
which was reversed with flumazenil just prior to cesarean section. Masui 1994;43:572 – 4.
[187] Bailey B. Are there teratogenic risks associated with antidotes used in the acute management
of poisoned pregnant women? Birth Defects Res A Clin Mol Teratol 2003;67:133 – 40.
[188] Richard F, Autret E, Bardol J, et al. The use of flumazenil in a neonate. J Toxicol Clin Toxicol
1991;29:137 – 40.
[189] Dixon JC, Speidel BD, Dixon JJ. Neonatal flumazenil therapy reverses maternal diazepam.
Acta Paediatr 1998;87:225 – 6.
[190] Collins S, Carter JA. Resedation after bolus administration of midazolam to an infant and its
reversal by flumazenil. Anaesthesia 1991;46:471 – 2.
[191] Brogden RN, Goa KL. Flumazenil. A reappraisal of its pharmacological properties and
therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991;42:1061 – 89.
[192] Kreuer S, Biedler A, Larsen R, et al. The Narcotrend: a new EEG monitor designed to measure
the depth of anaesthesia. A comparison with bispectral index monitoring during propofol-
remifentanil-anaesthesia. Anaesthetist 2001;50:921 – 5.
[193] Ortolani O, Conti A, di Filippo A, et al. EEG signal processing in anaesthesia: use of a neural
network technique for monitoring depth of anaesthesia. Br J Anaesth 2002;88:644 – 8.
[194] Schultz B, Grouven U, Schultz A. Automated classification algorithms of the EEG monitor
Narcotrend for routinely recorded EEG data from general anaesthesia: a validation study.
Biomed Tech (Berl) 2002;47:9 – 13.
[195] Campo R, Montserrat A, Brullet E. Transnasal gastroscopy compared to conventional
gastroscopy: a randomized study of feasibility, safety and tolerance. Endoscopy 1998;30:
448 – 52.
[196] Appleyard M, Glukhovsky A, Swain P. Wireless-capsule diagnostic endoscopy for recurrent
small-bowel bleeding. N Engl J Med 2001;344:232 – 3.
sedation and analgesia during pregnancy 31

[197] Ramirez FC, Shaukat MS, Young MA, et al. Feasibility and safety of string, wireless capsule
endoscopy in the diagnosis of Barrett’s esophagus. Gastrointest Endosc 2005;61:741 – 6.
[198] Ahlquist DA, Shuber AP. Stool screening for colorectal cancer: evolution from occult blood
to molecular markers. Clin Chim Acta 2002;315:157 – 68.
[199] Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Fecal DNA versus fecal occult blood for
colorectal-cancer screening in an average-risk population. N Engl J Med 2004;351:2704 – 14.
[200] Lefkovitz Z, Shapiro R, Koch S, et al. The emerging role of virtual colonoscopy. Med Clin
North Am 2005;89:111 – 38.
[201] American College of Radiology. MR safety and sedation. In: 1998 American College of
Radiology Standards. Reston (VA)7 American College of Radiology; 1998. p. 457.
[202] Chan YL, Chan AC, Lam WW, et al. Choledocholithiasis: comparison of MR cholangiography
and endoscopic retrograde cholangiography. Radiology 1996;200:85 – 9.
[203] Seidman DS, Heyman Z, Ben-Ari G, et al. Use of magnetic resonance imaging in pregnancy
to diagnose intussusception induced by colon cancer. Obstet Gynecol 1992;79:822 – 3.
[204] Colletti PM, Sylvestre PB. Magnetic resonance imaging in pregnancy. Magn Reson Imaging
Clin N Am 1994;2:291 – 307.
[205] Kanal E, Borgstede JP, Barkovich AJ, et al. American College of Radiology white paper
on MR safety. AJR 2002;178:1135 – 47.