Yes (1) Moore and McBride (1978) Nortriptyline 6.1240 PO.

Yes (2) Wisner et al. (1993) Oxazepam 8.40.PO.

Yes (3) Tomson et al. (1979) Source: Little BB. Obstet Gynecol 1999; 93 93: 858.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , pleak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared with nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV, intravenous; IM, intramuscular.

aControl groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female controls combined.

Antidepressants 183.

184.

Table 10.2 Summary of psychotropic exposure during the first trimester Summary of psychotropic exposure during the first trimester Psychotropic use during pregnancy Psychotropic use during pregnancy Total Elective Miscarriages Live Anomalies Source abortions births n (%) European networka Tricyclics Amitriptyline 118.

18.10.85.1.1.2.

Clomipramine 134.

20.22.87.2c 2.3.

Imipramine 30.1.3.27.2.7.4.

Nontricyclics Amineptine 40.7.7.25.1.4.0.Fluoxetine 96.15.13.65.2.3.1.

Fluvoxamine 66.9.6.50.1.2.0.Maprotiline 107.

17.11.77.2.2.6.

Mianserin 48.5.7.37.1.2.7.

Viloxazine 23.4.2.17.0.

0.

Meta-a.n.a.lysisb Combined

830.

22.2.0.Bupropion

72.0.

0.

Chan et al., 2005 Fluoxitine

300.

9.3.0.Chambers et al., 1996; Goldstein, 1995; Patsuzak et al., 1993 Paroxetine

222.

9.4.1.

Kulin et al., 1998 Trazodone/Nefazodone

121.

2.1.7.

Einarson et al., 2003 Venlafaxine

125.

2.1.6.

Einarson et al., 2001 aEuropean Network of Teratology Services Surveillance of Psychotropics in Pregnancy, Adapted from McElhatton et al., 1996.

bEinarson and Einarson, 2005.

, not a.n.a.lyzed.

Note: Background risk is 3.55%.

cExcludes one case of Down syndrome.

Antidepressants 185.

In a review of the use of psychotropics during pregnancy, Miller (1994a) found no increased risk of teratogenic effects from the use of tricyclics during pregnancy.

However, tricyclics may have both fetal and neonatal effects, such as tachycardia, cyanosis, and other withdrawal symptoms (Miller, 1996; Prentice and Brown, 1989).

Tricyclics may also cause adverse maternal effects, such as hypotension, constipation, sedation, tachycardia, and light-headedness (Miller, 1996).

IMIPRAMINE.

Imipramine is the prototype of tricyclic compounds and is quite effective in the treatment of endogenous depression. It has potent anticholinergic activity. There is little information regarding its safety during pregnancy, and those studies that are available contain only a few cases of first-trimester imipramine exposure during pregnancy.

However, there is no indication that imipramine causes significant teratogenic effects (Banister et al et al., 1972; Crombie et al et al., 1972; Heinonen et al et al., 1977; Idanpaan-Heikkila and Saxen, 1973; Kuenssberg and Knox, 1972; Miller, 1994a; Rachelefsky et al et al., 1972; Scanlon, 1969). There were 30 cases of first-trimester imipramine exposure recently reported, and the frequency of anomalies was not increased (McElhatton et al et al., 1996) (see Table 10.2).

Although limb reduction defects were reported by Morrow (1972) to be a.s.sociated with imipramine use during gestation, these observations were, most authorities believe, coincidence, and not causal. Surveillance groups in the USA and Canada examined the histories of hundreds of women who delivered children with limb reduction defects, and concluded that there was insufficient evidence to suggest a cause-and-effect relationship with imipramine (Banister et al et al., 1972; Rachelefsky et al et al., 1972). Withdrawal symptoms (transient respiratory, circulatory, and neurological adaptation abnormalities) were reported in three neonates whose mothers were exposed to imipramine during late pregnancy (Eggermont et al et al., 1972).

Animal studies indicate an increased frequency of congenital anomalies among the offspring of mice, rabbits, and hamsters who received imipramine in doses several times greater than those used in humans (Guram et al et al., 1980; Harper et al et al., 1965; Jurand, 1980), but not at lower doses (Harper et al et al., 1965; Hendrickx, 1975; La.r.s.en, 1963; Wilson, 1974). Changes in development and behavior were observed among the offspring of pregnant rats given one to five times the human dose of imipramine (Ali et al et al., 1986; Coyle, 1975; Jason et al et al., 1981). The relevance of these findings to clinical use in humans is unclear.

AMITRIPTYLINE.

Amitriptyline is as efficacious as imipramine for depression, but has marked anticholinergic and sedative activity. Among 427 infants born to mothers who took amitriptyline the frequency of birth defects (25, or 5.9 percent) was not increased (Rosa, personal communication, cited in Briggs et al et al., 2004), but this study is not peer reviewed. One of 89 infants in another study was malformed, and is within the rate for the general population (McElhatton et al et al., 1996).

The Collaborative Perinatal Project included 21 pregnant women treated with amitriptyline during the first trimester, and there was no increase in congenital malformations noted among the offspring (Heinonen et al et al., 1977). The European Network of 186 186 Psychotropic use during pregnancy Teratology Services reported 118 first-trimester exposures to amitriptyline with no increased frequency of malformations (McElhatton et al et al., 1996; see Table 10.2).

Depression of the central nervous system, although transient, has also been reported in a newborn whose mother was exposed to amitriptyline throughout gestation (Vree and Zwart, 1985). Note that the mother had serum levels in the moderately toxic range, whereas the infant's levels were severely toxic.

Animal teratology studies are not consistent. Thus, the relevance of these findings in animals to therapeutic use in humans is unknown.

DESIPRAMINE.

Desipramine is an active metabolite of imipramine used to treat depression. The anticholinergic and sedative effects of desipramine are less than those of imipramine. Among 31 infants whose mothers filled prescriptions for desipramine during the first trimester, there was one malformed infant (Rosa, personal communication, cited in Briggs et al et al., 2004). Neonatal withdrawal symptoms have been observed with desipramine when taken throughout gestation (Webster, 1973).

NORTRIPTYLINE.

Nortriptyline is chemically similar to amitriptyline. Two (3.3 percent) of 61 infants whose mothers had prescriptions for nortriptyline had birth defects (Rosa, personal communication, cited in Briggs et al et al., 2004). However, this study was not peer reviewed.

The active precursor of nortriptyline, amitriptyline, is discussed above. There is a single case report of a newborn with limb reduction anomalies and a dermoid cyst born to a mother who was treated with 30 mg nortriptyline daily in the early first trimester (Bourke, 1974). This is probably not a causal relationship. Maternal use of nortriptyline has been a.s.sociated with transient urinary retention in the newborn (Shearer et al et al., 1972).

DOXEPIN.

Doxepin has the same characteristics as the other tricyclics. Doxepin is as effective as imipramine and amitriptyline in treating depression, although it has a stronger sedative effect than the other two drugs. No reports have been published on studies of congenital anomalies among the infants born to women treated with doxepin during the first trimester. The frequency of congenital anomalies was not increased among rats and rabbits exposed to doxepin during embryogenesis (Owaki et al et al., 1971a,b). However, at doses 40 to 100 times those used in humans, an increase in fetal loss and neonatal death was found.

PROTRIPTYLINE, AMOXAPINE, AND CLOMIPRAMINE.

There are no available teratologic studies in animals or epidemiological studies of malformations among the newborns of pregnant women treated with these tricyclic agents.

No data on protriptyline use in pregnancy are published. Amoxapine is a metabolite of loxapine, an antipsychotic and antidepressant. Among 19 infants, there were three (15.8 percent) with congenital anomalies (Rosa, personal communication, cited in Briggs et et al al., 2004), which seems high compared to the expected rate of 5.3 percent. However, this study was not peer reviewed and this is a very small number of exposed infants.

Antidepressants 187.

The frequency of congenital anomalies was not increased among 134 pregnancies exposed to clomipramine during the first trimester (McElhattan et al et al., 1996; see Table 10.2). Seizures and abnormalities of perinatal adaptation have been reported in clomipramine-exposed newborns (Cowe et al et al., 1982; Ostergaard and Pedersen, 1982).

Withdrawal symptoms (increased irritability, alternating hypertonia and hypotonia, hyperreflexia, cyanosis, and hypothermia) were described in a newborn 1 day after delivery; these resulted from clomipramine use by the mother during late pregnancy (Boringa et al et al., 1992). An increased frequency of central nervous system and other anomalies was found among the offspring of pregnant mice exposed to clomipramine in doses 36 times those used in humans (Jurand, 1980). Persistent changes of behavior were found in the offspring of pregnant rats treated with this agent in doses greater than those used clinically (de Ceballos et al et al., 1985; Drago et al et al., 1985; File and Tucker, 1983).

MAPROTILINE.

Maprotiline is a tetracyclic antidepressant. The frequency of congenital anomalies was not increased among 107 pregnancies exposed to maprotiline during the first trimester (McElhatton et al et al., 1996; see Table 10.2). Teratology studies in animals have failed to demonstrate any adverse fetal effects (Esaki et al et al., 1976; Hirooka et al et al., 1978).

Newer antidepressants or selective serotonin re-uptake inhibitors This relatively new cla.s.s of antidepressants includes fluoxetine, paroxetine, and sertraline. Fluoxetine (Prozac) is probably the most commonly used and best-known agent in this group. This relatively new cla.s.s of antidepressants includes fluoxetine, paroxetine, and sertraline. Fluoxetine (Prozac) is probably the most commonly used and best-known agent in this group.

Meta-a.n.a.lysis of seven published studies revealed no increased risk for congenital anomalies among infants whose mothers took newer antidepressants (Table 10.2) in the first trimester (Einarson and Einarson, 2005). Recently, problems in neonatal adaptation (Chambers et al et al., 1996; Costei et al et al., 2002; Kallen, 2004; Oberlander et al et al., 2004) and symptoms of a neonatal withdrawal syndrome (Nordeng et al et al., 2001) were described in infants born to women who used SSRIs in late pregnancy. No adequate studies have been published of infants born following exposure to escitalopram, venlafaxine, or duloxetine during pregnancy. Of 125 infants born to women who took venlafaxine during pregnancy, the frequency of congenital anomalies was not increased. However, the neonatal behavioral alterations noted above may comprise a withdrawal syndrome.

Some authorities have anecdotally noted similar symptoms of abstinence among adults who abruptly discontinue SSRI use. Furthermore, it is suggested by some psychiatrists that infants antenatally exposed to SSRIs, and perhaps other antidepressants, remain at risk for depression as teenagers and adults.

FLUOXETINE.

Fluoxetine (Prozac) acts primarily by inhibiting serotonin reuptake by neurons (Goldstein et al et al., 1991). Although there are no large epidemiological studies of fluoxetine in pregnant women, the manufacturer's registry has collected outcome information on 184 pregnancies exposed to this agent (Goldstein et al et al., 1991). Of these, 35 resulted in spontaneous abortions and 41 pregnancies were electively terminated. Of the 114 live-born infants, 93 were normal, nine were premature, nine had perinatal 188 188 Psychotropic use during pregnancy complications, and three had malformations of a nonspecific type. One of these infants had major cardiac malformations and was born to a mother who took fluoxetine in the second trimester, after the period of embryonic cardiac development. The spontaneous abortion rate of 19 percent and malformation rate of 23 percent is similar to the rate of these complications in the general population.

A review of pregnancy outcomes following first-trimester exposure to fluoxetine, found no increase in congenital malformations (Pastuszak et al et al., 1993). Similarly, there was no increased frequency of anomalies among 96 first-trimester-exposed pregnancies in a European study (McElhatton et al et al., 1996; see Table 10.2). Meta-a.n.a.lysis indicated no increased risk of congenital anomalies among 300 infants exposed to fluoxetine during the first trimester (Einarson and Einarson, 2005). The frequency of congenital anomalies was not increased among 174 infants whose mothers used fluoxetine throughout pregnancy (including first trimester) (Chambers et al et al., 1996). The rate of preterm delivery was significantly increased in the fluoxetine-exposed group. No differences in IQ or neurodevelopment were found compared to matched controls at 1.53 years of age among 43 children whose mothers took fluoxetine during pregnancy (Nulman and Koren, 1996).

Problems in neonatal adaptation have been reported with SSRI use in late pregnancy.