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screening instruments and structured interviews, has determined the first trimester was originally recommended, but one study
that rates of depression are substantial, particularly in the second of 148 women on lithium suggests that the incidence of major
malformations is similar to that in a control group.21 Ebstein
and third trimesters. Depression in the first trimester seems to
occur as commonly in pregnant women as in the nonpregnant anomaly (right ventricular hypoplasia, patent ductus arteriosus,
population (7.4% in this study). The figure rises to 12% for the tricuspid incompetence) has been associated with maternal
second and third trimesters, perhaps indicating that late-stage lithium exposure. However, one review of four case-control stu-
pregnancy may be a risk factor for depression. dies involving more than two hundred infants with Ebstein
The authors15 point out that even though many women are anomaly22 found none had been born to women taking lithium,
affected, it is not often appreciated that depression leads to a so the risk is very low.
significant impairment in function. Depression is a leading It is recommended that women with a single past episode of
cause of disability adjusted life years (years of life not lived due mania, whose condition is currently stable, consider discontinu-
ing lithium therapy before conception.22 Those with less stable
to premature death, and years of productive life lost due to dis-
ability). An estimated 10“15% of all women experience depres- disorders are advised to attempt temporary cessation of the drug
sion during pregnancy and the postpartum period.15 One third of during the embryonic period (4“12 weeks™ gestation). Since
women who develop depression in pregnancy have their first severely affected women with bipolar disorders may be at risk if
episode of the disorder at this time. Physicians often fail to detect therapy ceases, they should continue to take lithium. Antenatal
counseling and prenatal diagnosis should be offered.22
depression in pregnancy because even healthy women report
symptoms during pregnancy that are associated with depression.
These symptoms include disturbed sleep, change in appetite, and
Tricyclic antidepressants
low energy. In addition, pregnancy-related medical conditions
such as anemia, gestational diabetes, and thyroid dysfunction In the past, there were concerns that the use of tricyclic anti-
depressants (TCAs) led to phocomelia,6 but this concern has not
may mimic symptoms of depression. As a result there may be a
delay in accurate diagnosis. been borne out. The Finnish Registry of Congenital Malfor-
mations23 reported no increase in congenital malformations in
Depression is a major health problem for the world, and for
pregnant women in particular.16 Depression not only increases fetuses exposed to imipramine in the first trimester. Neonatal
antidepressant withdrawal symptoms have been observed,24
the risk of physical and social disability but is also associated with
bad outcomes in pregnancy. These outcomes include poor health along with anticholinergic side effects (constipation, urinary
behavior, risk-taking behavior, preeclampsia, and an increased retention).
risk of progression to postpartum depression. There are signifi- The mechanism of action of TCAs was thought to be related to
cant associations between depression and increased nausea and their ability to inhibit reuptake of neurotransmitters, especially



365
5 Other disorders


rates of miscarriage have been reported,29 one study found that
norepinephrine, into the presynaptic terminal, thus increasing
the amount available for synaptic transmission. The efficacy of fluoxetine taken during pregnancy did not increase the risk of
spontaneous loss or major anomalies of the fetus.30 That same
reuptake inhibitors for other transmitters (e.g. serotonin) in treat-
ing depression, combined with a better understanding of the study, however, indicated that the number of perinatal compli-
complexities of neurophysiology, means that simple models cations was greater in women who took the drug during the
represent only part of the explanation. Alterations in receptor third trimester compared with those who took it only in the
sensitivity are likely to play a role, explaining the delay of two to first and second trimester. An editorial accompanying this pub-
three weeks in clinical response. lication concluded that the evidence does not prove that fluox-
etine and TCAs are unsafe for pregnant women.31 Their use
Anticholinergic side effects occur in up to 15% of patients and
they are prominent in those who take overdoses of TCA. involves a calculated risk, however, because of their uncertain
Anesthesiologists may be asked to help manage such patients side effects.
when pregnancy is a complicating factor. I am aware of one Initial work with sertraline suggests that it is useful in the
unpublished case of a fatal overdose in a pregnant woman treatment of postpartum depression and a recent Cochrane
whose baby was delivered alive, only to die later. Features of Database review revealed that sertraline reduced the recurrence
anticholinergic poisoning include dilated pupils, agitation, and of postnatal depression and the time to recurrence when com-
pared with placebo.32 A single case report suggests that levels in
delirium. Convulsions and hyperpyrexia may occur. The features
of TCA overdose are principally those of rhythm and conduction breast milk vary substantially over a 24-hour period, with no
detectable levels in the infant.33 Selective serotonin reuptake
disturbance: all forms have been described. Prolonged QT and
QRS segments point to cardiac involvement. Treatment of signi- inhibitors and their metabolites variably inhibit cytochrome
ficant dysrhythmias has included hyperventilation,25 which helps P450 2D6, which is the enzyme responsible for the metabolism
correct the acidosis. Sodium bicarbonate has been used,26 of other drugs, such as antidysrhythmics, b-blockers, antihyper-
although enthusiasm for its empirical use has waned.27 tensives, and codeine. Women with a severe psychiatric illness
The principal side effects of the TCAs result from their non- may be taking multiple psychoactive drugs, with the potential for
specific interactions with a range of receptors, including choli- further interactions. These drugs include thioridazine, clozapine
nergic, histaminergic, serotonergic, and dopaminergic receptors. (an antipsychotic of the dibenzazepine group), and TCAs. To
date, there is little evidence of clinically important interactions.34
The secondary amine TCAs (e.g. nortriptyline, desipramine) are
Importantly, SSRIs are safe in overdose,35 but can interact with
relatively selective norepinephrine reuptake inhibitors with a
more benign side effect profile than the tertiary amines. The a- monoamine oxidase inhibitors to produce the sometimes lethal
serotonin syndrome.36
adrenergic receptor blockade seen with TCAs can potentiate anti-
hypertensive medication. This is particularly true for drugs that Neonatal and pregnancy outcome data following maternal
act in a similar manner, such as prazosin. drug use during pregnancy were obtained from the Swedish
Medical Birth Registry.37 These data were compared to data
Because all TCAs lower the seizure threshold, care must
be taken when they are given to preeeclamptic patients. Further- from all infants in the registry after adjustment for birth year,
more, extra vigilance is demanded when large volumes of local maternal age, parity, and maternal smoking in early pregnancy. It
anesthetic are required, such as when establishing epidural identified 997 infants whose mothers had received antidepres-
anesthesia for C/S, because otherwise safe doses may lead to sant therapy after the first antenatal visit. The majority of mothers
seizure activity. had taken SSRIs (558) while 395 had used TCAs. Women who had
taken antidepressants were statistically more likely to have pre-
term birth (odds ratio (OR) ¼ 1.96), low birth weight (OR ¼ 1.98),
Selective serotonin reuptake inhibitors (SSRIs)
and small for gestational age babies (OR ¼ 0.83). These effects
Serotonin reuptake inhibitors are the mostly commonly pre- were similar between SSRIs and TCAs. There was an increase in
neonatal respiratory distress (OR ¼ 2.21), neonatal hypoglycemia
scribed antidepressants used in women of childbearing age. The
(OR ¼ 1.62), low Apgar scores (OR ¼ 2.33), and neonatal convul-
SSRIs have not been associated with an increased risk for con-
sions (OR ¼ 4.7). All of these effects were greater in neonates
genital malformations in children exposed to them during the
first trimester. There is also no evidence that children exposed whose mothers had taken TCAs compared to SSRIs but these
to this class of drug in utero experience long-term problems such could have been random effects. Of the SSRIs, paroxetine pro-
as developmental delay.20 Serotonin (5-hydroxytryptamine, 5- duced the biggest difference, but it was not statistically signifi-
HT) is a regulatory neurotransmitter, with predominantly inhibi- cant and may have reflected a relatively small number of women
using paroxetine.37 The effects seen in newborns might be related
tory effects. Serotonin inactivation occurs chiefly by reuptake,
to SSRI withdrawal.37 Table 20.3 lists the symptoms that have
which is selectively blocked by SSRIs. As a result, serotonin levels
rise in the postsynaptic cleft, leading to desensitization of been attributed to neonatal withdrawal following maternal inges-
presynaptic autoreceptors, increased serotonin release, and tion of SSRIs. It is probable that neonatal withdrawal effects
increased neurotransmission.28 would be minimized by using the lowest effective maternal
Most of the data on teratogenesis concern fluoxetine, but dose in the third trimester, while breast milk transfer can be
there is no evidence to date that women taking the drug are at treated by stopping or reducing the dose of SSRI, or by using
greater risk for fetal malformations or stillbirth. Although higher formula milk.



366
Chapter 20



Table 20.3 Frequent neonatal symptoms reported Table 20.4 Causes of death in serotonin syndrome
in association with maternal SSRI ingestion
1. Rhabdomyolysis
Withdrawal Breast-milk 2. Disseminated intravascular coagulation
Symptoms syndrome transfer 3. Respiratory distress syndrome
4. Cardiovascular collapse
Agitation/jitteriness 15 4
Poor feeding 7 4
Hypotonia 7 1
convulsion, and coma. Meperidine is thought to be the only com-
Sleepiness/lethargy 0 3
mon opioid to elicit such a reaction. Type II is depressive, character-
3a
Gastrointestinal symptoms 3
ized by hypotension, respiratory depression, and coma.
Total reports 26 13
Monoamine oxidase inhibitors are known teratogens in ani-
mals, but their effects in humans are unclear. Importantly for
a
In one case the symptoms may have been from breast-milk transfer.
anesthesiologists, severe hypertension may also follow adminis-
Data derived from 26 reports of neonates with symptoms attributed
tration of indirect-acting pressor agents, such as ephedrine and
to withdrawal effects due to maternal third trimester ingestion of SSRIs
metaraminol.41 Treatment with MAOIs leads to accumulation of
(paroxetine 10, sertraline 7, fluoxetine 7, citalopram 2). Table 20.3
presents the most frequently reported reactions. Other reactions norepinephrine in sympathetic nerve terminals, and indirect-act-
included convulsions, tremor, fever, and respiratory disorders (respirat- ing agents can release large quantities of this and other transmit-
ory depression, apnea, tachypnea). Two babies had marked extensor ters. Thus, an exaggerated hypertensive response may ensue, and
posturing with back-arching. The usual day of onset, if reported, was the
vigorous a-adrenoreceptor blockade (e.g. with phentolamine)42
day of birth, but ranged from zero to four days of age. The symptoms
may be required. Infusions of direct-acting agents such as epi-
resolved in two to three days in most cases. In addition, 13 reports have
nephrine are preferred for maintenance of blood pressure,
been received of neonatal adverse effects probably resulting from breast-
despite concerns in respect of uterine artery constriction.
milk transfer of an SSRI (sertraline 9, paroxetine 2, fluoxetine 2). There
Caution is needed because receptor hypersensitivity may develop
was some overlap of the symptoms resulting from drug transfer into
in these patients.43
breast milk and from drug withdrawal (see table). However, sleepiness
A case report44 describes the use of opioid- and epinephrine-
was reported only with breast milk transfer, and in two cases the baby
free epidural analgesia for labor in a woman who had consistently
slept for prolonged periods.
From Australian Adverse Drug Reactions Bulletin 2003; 22: issue 4 used phenelzine, a first-generation MAOI, for six years. Careful
establishment of regional blockade obviated the need to admin-
ister vasopressors. Invasive arterial monitoring was instituted
once the decision was made to proceed to C/S. Fentanyl had
Another study examined neonatal behavior comparing 17 been used uneventfully for two general anesthetics in the past,
SSRI-exposed neonates to 17 nonexposed neonates.38 It was but it was not needed for this delivery. Epidural morphine pro-
found that SSRI-exposed infants were healthy, but showed vided postoperative analgesia without incident and the newborn
greater disruption of neurobehavior: specifically tremulousness appeared normal.
and all measures of state and sleep organization. The implica- Monoamine oxidase inhibitors inhibit degradation of seroto-
tions for later development were unclear and the effects may nin, whereas SSRIs and TCAs inhibit serotonin reuptake. When
well be short lived; however, further study is required.38 The combined, there is a synergistic effect, which produces a hyper-
US Food and Drug Administration (FDA) has not approved serotoninergic state, most commonly as a result of concurrent
any psychotropic drug for use in pregnancy. Paroxetine, in parti- or temporally related consumption of MAOI and SSRI. This is
cular, has been identified by the FDA as being associated with a rare but occasionally leads to death from rhabdomyolysis, disse-
two fold increase in congenital heart disease (mostly atrial and minated intravascular coagulation, adult respiratory distress syn-
ventricular septal abnormalities) if consumed in the first tri- drome, and cardiovascular collapse (see Table 20.4).45 Secondary
mester.38 FDA labeling of antidepressant drugs is the cause of effects of the hyperthermia that follows the centrally mediated
ongoing controversy (see www.fda.gov/ohrms/dockets/dailys/ muscle rigidity have been successfully treated with muscle
04/sep04/092304/04n-0338-c00001-vol1.pdf). relaxation, sedation, and controlled ventilation.35
Second-generation MAOIs inhibit only the A subtype of MAO.
Their pharmacology was reviewed by McFarlane.46 Moclobemide
Monoamine oxidase inhibitors (MAOIs)
is one drug in this group and is classified as a reversible selective
As with other psychoactive drugs, there is little in the obstetric inhibitor of monoamine oxidase A. Its efficacy seems comparable
anesthesia literature about these agents. It is well known that first to that of SSRIs, with one study suggesting rapid improvement in
quality of life and social functioning.47 No important interactions
generation MAOIs, which bind irreversibly to both A and B subtypes
of monoamine oxidase (MAO), can produce lethal excitatory or with TCAs are reported but animal work suggests that meperi-
depressive interactions with meperidine.39,40 The former interac- dine is contraindicated.48 There is also the potential for prolon-
tion, called type I, is thought to be the result of serotoninergic activity gation or enhancement of analgesics and anesthetic induction
agents.46
and is characterized by agitation, headache, rigidity, hyperthermia,



367
5 Other disorders


Electroconvulsive therapy
Table 20.5 Anesthetic considerations for electroconvulsive
Electroconvulsive therapy (ECT, electroshock) is a historically therapy in pregnancy
important and highly effective form of treatment in psychiatric
1. Cease anticholinergic medication
practice. It is particularly useful where psychotropic medication
2. Monitor uterine contractions
has failed or when urgent control of an illness is required. Suicidal
3. Rehydrate
or violent patients (see earlier), or those whose condition poses a
4. Sodium citrate
threat to their life (e.g. the catatonic or profoundly depressed may
5. Lateral uterine displacement after 20 weeks™ gestation
refuse to eat or drink) can improve rapidly with ECT. Pregnant
6. Fetal monitoring after 20 weeks™ gestation
patients may need ECT for urgent control of symptoms, with impli-
7. Tracheal intubation after first trimester
cations for the anesthesiologist. Two reviews49,50 attest to the efficacy
8. Normocapnia
and relative safety of the practice, which has the added advantage
9. Observe for contractions and bleeding post-ECT
that psychotropic medication can be minimized or avoided. Its
mechanism of action is unclear, but ECT is thought to increase levels
of neurotransmitters more rapidly than is possible with oral therapy. duration of action and propensity for excitatory phenomena, is
For certain delusional patients, ECT may be seen as punishment. a better drug. Regardless of agent, rapid sequence induction with
The practice of inducing convulsions was begun by von cricoid pressure and tracheal intubation are mandatory after the
Meduna51 following the shrewd observation that epileptic first trimester to protect the airway. Similarly, lateral uterine dis-
patients rarely developed schizophrenia. It was known that psy- placement should be instituted from about 20 weeks™ gestation,
chiatric patients became briefly asymptomatic after a seizure, using a wedge under the right hip. Hyperventilation with 100%
regardless of its cause. Initial attempts to produce seizure activity oxygen prior to ECT may enhance the quality of the seizure, but
involved i.v. injections of pentylenetetrazol (Metrazol). It was severe respiratory alkalosis must be avoided.50 Uterine contrac-
some years, however, before a reliable means of inducing con- tions and FHR must be monitored before and after ECT, and the
vulsions was devised by Cerletti.52 woman must be observed for vaginal bleeding after the convul-
The earliest ECT was quite barbaric, with serious fractures and sion. Provided that all precautions are taken, ECT is usually safe in
other injuries following the unmodified convulsions. Interestingly, pregnancy; however, one report describes status epilepticus fol-
the only subset to improve were the depressed schizophrenics, lowing ECT in a woman at 22 weeks™ gestation which led to multi-
whose mood improved; the schizophrenia was unaffected. organ failure and fetal demise. The decision to embark on ECT
General anesthesia of short duration has made the experience treatments is clearly one to be made in consultation with the
safer and more pleasant. Current practice includes establishment obstetrician, psychiatrist, and anesthesiologist.55
of i.v. access, preoxygenation, induction of anesthesia with metho-
hexital and a small dose of succinylcholine (e.g. 0.5 mg/kg) to
Panic disorder
modify the peripheral expression of the seizure.
The first use of ECT in pregnancy was inadvertent. A psychotic This disorder, first described by Klein in 1964, is characterized by:
patient was known to have an abdominal mass, but the fact that (1) sudden, spontaneous, unexpected feelings of terror and anxi-
this was a gravid uterus was not appreciated until later. The ety; (2) autonomic equivalence of anxiety; (3) desire to flee the
pregnancy went to term and the child was developmentally nor- situation and return to a safe place; and (4) phobic avoidance of
mal.53 A literature review50 uncovered 300 case reports over the the places where such attacks occur.56
period 1942“91. Complications occurred in 28 cases “ 5 in the first This sometimes disabling syndrome often begins in the third
trimester, 11 in the second, 8 in the third, and the remainder at decade, when many women conceive. Interestingly, some find
that their symptoms improve during pregnancy.57 Attacks typi-
unspecified times. Fetal dysrhythmias occurred in five cases but
were evanescent. One woman who received a total of 35 courses cally take place in restaurants, crowded stores, supermarkets, and
of ECT delivered prematurely. Five instances of vaginal bleeding on public transport. Besides the distress of the attack itself, it is
following treatment were reported in this series. One of these was possible to develop anticipatory anxiety about having another
thought to represent recurrent mild abruptio placentae, because episode. Furthermore, phobic avoidance may develop for the
there was associated transient hypertension with each course. A place or places where attacks have occurred; sufferers with severe
large retroplacental clot was found at C/S at 37 weeks™ gestation disease rarely leave home for years. An increased incidence of this
when vaginal bleeding began during labor.54 Postictal uterine disorder is seen in first-degree relatives of sufferers.58 Attempts at
contractions were noted for a brief time in two women, and four self-medication can lead to abuse of both alcohol and sedative
others went on to develop premature labor. drugs, while the risk of suicide approaches that for patients with a
major depressive illness.59
The review points out the areas of principal concern for the
anesthesiologist, namely aortocaval compression, fetal hypoxia,
pulmonary aspiration, and specific drugs for anesthesia.
Drug therapy
Recommendations for ECT during pregnancy are in Table 20.5.
Thiopental is safe in pregnancy but its potent anticonvulsant Cognitive“behavioral therapy is commonly employed in the
activity makes it less desirable. Methohexital, with a shorter management of this condition, but it is pharmacotherapy that



368
Chapter 20


Sympathetic support is called for, perhaps with pharmacologic
Table 20.6 Recommendations for benzodiazepine use assistance. Short-acting BZDs in small doses may help (e.g. i.v.
during pregnancy midazolam, one-milligram boluses until control is achieved).
Clonidine, which is a useful epidural analgesic may be worth
1. Before conception, carefully reevaluate pharmacotherapeutic
trying as an i.v. anxiolytic in doses of 25 mg. Sedation is likely
regimens.
once 100 mg is exceeded, although much larger doses have been
2. Taper the dose of benzodiazepines so that breakthrough symptoms
used for control of hypertension in pregnancy. Clonidine is safe in
of panic and/or withdrawal are avoided.
pregnancy with no harmful neonatal effects.64 Addition of cloni-
3. For patients on short-acting agents (e.g. alprazolam) who develop
dine to the epidural solution might achieve improved analgesia
recurrence, consider adding a tricyclic antidepressant.
and useful sedation simultaneously.
4. Consider switching patients on alprazolam to clonazepam, which
has a longer half-life and may decrease the incidence of rebound
anxiety.
Conclusion
Personality disorders, mood disorders, schizophrenia, and
most affects the patient seen by the obstetric anesthesiologist. adjustment disorders constitute the bulk of the psychiatric syn-
Selective serotonin reuptake inhibitors and TCAs are often dromes likely to present to the obstetric anesthesiologist. Many
used and are discussed earlier. The MAOIs may succeed when of the patients with these conditions will be on medications
other antidepressants fail, but there are no data to date concern- that may interact to a degree with anesthetic and analgesic
ing second-generation drugs (e.g. moclobemide). Phenelzine agents. In addition, the women themselves can be challenging
is very effective.60 Commonly prescribed drugs are benzodia- in view of their abnormal psychology, complicated further by
zepines (BZD), particularly alprazolam and clonazepam. the stress of pregnancy, the pain of labor, and the distress
Benzodiazepines act by mimicking both the principal inhibitory that can accompany the difficult decisions that often need to
neurotransmitter in the brain, g-aminobutyric acid (GABA), and be made.
glycine, the major inhibitory transmitter in the spinal cord and An even more difficult challenge is the patient with a psycho-
brain stem. tic illness, control of which may be affected adversely by preg-
Benzodiazepines are potentially harmful to the fetus, although nancy. Consultation with the obstetrician and, importantly,
evidence from studies is scarce. Exposure to BZD in the first attending psychiatrist, is necessary if the illness is to be under-
four months of pregnancy does not significantly increase the stood fully. After consultation, it is possible to devise a plan for
risk of oral clefting, as determined by a case-control study.61 safe conduct of anesthesia and analgesia. It is important to seek
Recommendations for BZD use in pregnancy are summarized psychiatric advice on the best approach to each individual
in Table 20.6. patient.65 Not all anesthesiologists are skilled in this area, and
Nonpharmacologic treatment, such as cognitive“behavioral time spent in consultation before entering the labor suite may
therapy, should be first-line treatment in pregnant women with be invaluable.
generalized anxiety disorder, or panic disorder.62
In December 1991, the Upjohn voluntary reporting system
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