PAROXETINE AND SERTRALINE.

Paroxetine and sertraline are listed as FDA category B drugs. The frequency of congenital anomalies was not increased above background among 394 infants exposed to paroxetine during the first trimester (Diav-Citrin et al et al., 2002; Ericson et al et al., 1999; Inman et al et al., 1996; Kulin et al et al., 2002; McElhatton et al et al., 1996; Wilton et al et al., 1998).

However, as recently as July 2006, the manufacturer of Paxil (paroxetine) reported that first trimester use increased the risk of birth defects by between two and three times, with the risk of congenital heart defects being doubled. This contradicts prior studies of the drug's use during the first trimester.

Similarly, the frequency of birth defects was not increased among infants born to 326 women who took sertraline during the first trimester (Chambers et al et al., 1999; Hendrick et al et al., 2003; Kulin et al et al., 2002; Wilton et al et al., 1998).

Problems in neonatal adaptation termed the 'neonatal adaptation syndrome' was described in infants exposed to paroxetine in late pregnancy (Costei et al et al., 2002).

CITALOPRAM.

Citalopram is an SSRI used to treat depression. Among 125 pregnancies with 114 live born infants whose mothers took citalopram during the first trimester, there was one (0.9 percent) congenital anomaly (Sivojelezova et al et al., 2005). The authors concluded that the drug was not a.s.sociated with congenital anomalies with exposure during early pregnancy, but that use of citalopram in late pregnancy was a.s.sociated with increased frequency of poor neonatal adaptation, recently reported with other SSRIs (Chambers et al et al., 1996; Costei et al et al., 2002; Kallen, 2004; Nordeng et al et al., 2001; Oberlander et al et al., 2004).

Other nontricyclic antidepressants Data have been published for other nontricyclic antidepressants that are not discussed above. No increased frequency of congenital anomalies was found among 40, 66, 48, Antidepressants Antidepressants 189.

and 23 pregnancies exposed during the first trimester to amineptine, fluvoxamine, mianserin, and viloxazine, respectively (McElhatton et al et al., 1996; see Table 10.2).

BUPROPION AND TRAZODONE.

Burpropion is an antidepressant that is also used in tobacco smoking cessation treatment. It was not a.s.sociated with an increased risk of congenital anomalies among 354 infants born to women who used bupropion during the first trimester and reported to a registry, 12 (3.4 percent) of whom were malformed (Bupropoin Registry, 2004).

Bupropion is a category B drug.

Trazodone is an antidepressant that is also given for its sedative activity. First-trimester exposure to trazodone in 112 infants was not a.s.sociated with an increased frequency of congenital anomalies (Rosa, personal communication, cited in Briggs et al et al., 2004), although this study is not peer reviewed. In another investigation that was peer reviewed, 121 women took trazodone or nefazodone during the first trimester. The frequency of congenital anomalies was not increased above that expected in the general population (3.5 percent) (Einarson et al et al., 2003). Trazodone is a category C drug.

Monoamine oxidase inhibitors The monoamine oxidase inhibitors are also used for treating depression. There are no large epidemiological studies available regarding the safety of these agents during pregnancy. Only 21 pregnancies with early exposure to the monoamine oxidase inhibitors have been published, and there was an apparent increase in malformations a.s.sociated with the use of these agents (Heinonen et al et al., 1977). However, it is impossible to draw clinically useful information from such data because the sample size is too small.

Animal teratology studies undertaken with with monoamine oxidase inhibitors are not consistent, with some reporting no increase in the frequency of birth defects with tranylcypromine (Poulson and Robson, 1963), while others reported an increase in both the mortality rate and stillbirth rate in the isocarboxazid group (Werboff et al et al., 1961).

An increase in placental infarcts occurred in pregnant rats who received ip.r.o.niazid during gestation (Poulson et al et al., 1960). Decreased fertility was reported in the offspring of rats treated with nialamide (Tuchmann-Duplessis and Mercier-Parot, 1963). No animal teratology studies have been published on the monoamine oxidase inhibitor, phenelzine.

These agents are generally not used during pregnancy because of potential adverse maternal side effects, and are category C drugs. Women on drugs in this cla.s.s must follow a diet low in tyramine. Failure to do so may result in hypertensive crisis (Yonkers and Cunningham, 1993). Importantly, monoamine oxidase inhibitors given with meperidine, or other similar agents, may cause hyperthermia (Yonkers and Cunningham, 1993).

ANTIPSYCHOTICS.

Antipsychotics are used to treat psychosis of any cause, including psychotic depression, bipolar disorder, substance-induced hallucinations, or delirium-induced psychosis. 'Off-label' these medications are used to augment antidepressants and antianxiolytics. These drugs are continued only as long as the underlying cause of psychosis is present because 190 190 Psychotropic use during pregnancy of the tardive dyskinesia a.s.sociated with these medications. Antipsychotics were formerly called neuroleptics or major tranquilizers.

Commonly used antipsychotics or neuroleptic agents, with the exception of clozapine (Box 10.2), are dopamine antagonists (Yonkers and Cunningham, 1993). These agents have numerous side effects including anticholinergic effects such as constipation, dryness, and orthostatic hypotension, and extrapyramidal side effects such as akathisia (Miller, 1996; Yonkers and Cunningham, 1993). These agents may also cause marked sedation.

Antipsychotics may cause transient neonatal side effects including withdrawal symptoms and extrapyramidal dysfunction (hand posturing, tremors, and irritability) (Auerbach et al et al., 1992; Miller, 1994a, 1996; s.e.xson and Barak, 1989).

Two major confounders make it problematic to evaluate possible a.s.sociations of antipsychotics and congenital malformations. First, many of these agents are used for indications other than psychosis (hyperemesis, anxiety) where lower doses may be used (Yonkers and Cunningham, 1993). Second, the psychiatric disease itself may be a.s.sociated with an increased frequency of malformations (Elia et al et al., 1987).

Butyrophenones HALOPERIDOL.

Haloperidol is a butyrophenone derivative. It has pharmacological properties similar to the piperazine phenothiazines, although it is not chemically related to them. Haloperidol is used as a major tranquilizer to treat psychosis, Tourette's syndrome, mania, and severe hyperactivity. In lower doses than for psychosis, it is also used to treat nausea or anxiety.

In a cohort study of 98 pregnant women who received haloperidol for hyperemesis gravidarum (90 during early pregnancy), there were no obvious congenital anomalies or adverse fetal effects noted (van Waes and van de Velde, 1969). These patients received 0.6 mg haloperidol twice a day for differing durations, which is less than the dose typically used in the treatment of psychiatric illnesses. Among 56 infants whose mothers took haloperidol during the first trimester, the frequency of congenital anomalies was not increased (3, or 5.4 percent) (Rosa, personal communication, cited in Briggs et al et al., 2004).

Two cases of newborns with limb reduction malformations after haloperidol exposure during the first trimester have been published (Dieulangard et al et al., 1966; Kopelman et et al al., 1975), but a causeeffect relation cannot be made from such anecdotal observations.

Box 10.2 Commonly used antipsychotic agents Chlorpromazine (Thorazine) Trifluoperazine (Stelazine) Clozapine (Clozaril) Fluphen.a.z.ine (Prolixin, Permitil) Newer antipsychotics Haloperidol (Haldol, Decanoate) Amisulpride (Solian) Loxapine (Loxitane, Daxolin) Aripiperazole (Abilify) Mesoridazine (Serentil) Clozapin (Clozaril) Molindone (Moban, Lidone) Olanzapine (Zyprexa) Perphen.a.z.ine (Etrafon, Trilafon) Risperidone (Risperdal) Thioridazine (Mellaril) Sertindol (Serdolect) Thiothixene (Navane) Ziprasidone (Geodon) Antipsychotics 191.

Several researchers have noted an a.s.sociation between large doses of haloperidol in pregnant animals and adverse fetal effects and pregnancy losses (Druga et al et al., 1980; Gill et al et al., 1982; Szabo and Brent, 1974), but not at lower doses (Bertelli et al et al., 1968; Hamada and Hashiguchi, 1978). The pertinence of animal studies to the clinical use of haloperidol in human pregnancy is unclear.

LOXAPINE.

Loxapine is a dibenzoxazepine derivative used to treat schizophrenia. No information on the use of this tricyclic antipsychotic during pregnancy in humans has been published. In mice and rats whose mothers were treated with loxapine during embryogenesis, a low incidence of exencephaly and an increase in fetal loss was observed in only one mouse litter out of 20 studied (Mines.h.i.ta et al et al., 1970).

Phenothiazines Phenothiazines are related drugs with potent adrenergic-blocking action. Pharmacologic effects include central nervous system depression, prolonged effects of narcotic or hypnotic drugs, and hypotensive, antiemetic and antispasmodic activity.

CHLORPROMAZINE.

Chlorpromazine is a phenothiazine derivative used to treat psychoses and has tranquilizing and sedative effects. It is also used as an antiemetic during pregnancy. Two well-described side effects hypotension and extrapyramidal tract symptoms of this drug need special attention. The frequency of congenital anomalies was not increased among 140 infants born to women exposed to this agent during the first trimester of pregnancy (Heinonen et al et al., 1977). In a cohort study of 264 pregnant women who took chlorpromazine for hyperemesis gravidarum in the first trimester, the frequency of congenital anomalies was not increased (Farkas and Farkas, 1971). One study reported an increase in the frequency of congenital anomalies in offspring exposed to chlorpromazine compared to controls (Rumeau-Rouquette et al et al., 1977). However, the 3.5 percent incidence of malformations in the chlorpromazine group is no higher than is expected in the general population (3.55 percent). The frequency of congenital anomalies or pregnancy loss in 52 pregnancies was not increased among those exposed to chlorpromazine.

However, three infants were reported with respiratory distress delivered from mothers treated with 500600 mg per day (Sobel, 1960). A case of congenital defects involving the heart in a.s.sociation of phenothiazine use during gestation was reported (Vince, 1969), but this is anecdotal and its meaning unknown.

Transient newborn neurological dysfunction was reported by several investigators in a.s.sociation with chlorpromazine use during pregnancy (Hammond and Toseland, 1970; Hill et al et al., 1966; Levy and Wisniewski, 1974; Tamer et al et al., 1969). Extrapyramidal signs in exposed infants include muscle rigidity, hypertonia, and tremor.

Some investigators reported an increase in congenital anomalies in animals exposed to this antipsychotic during embryogenesis (Brock and von Kreybig, 1964; Jones-Price et al et al., 1983b; Singh and Padmanabhan, 1978; Yu et al et al., 1988), but others have not found such an increase (Beall, 1972; Jelinek et al et al., 1967; Jones-Price et al et al., 1983a; Robertson et al et al., 1980).

192.

Psychotropic use during pregnancy FLUPHEn.a.z.iNE.

Fluphen.a.z.ine is a piperazine phenothiazine that appears to be relatively safe to use during gestation. Among 226 infants whose mothers who took fluphen.a.z.ine (as an antiemetic) during the first trimester, the frequency of congenital anomalies was not increased (King et al et al., 1963). Extrapyramidal signs in the newborn were observed several weeks after delivery of a newborn exposed to fluphen.a.z.ine in utero in utero (Cleary, 1977) (Cleary, 1977) . .

Malformations were not increased in the offspring of pregnant rats exposed to this phenothiazine during organogenesis compared to controls (Jahn and Adrian, 1969) or in those exposed throughout pregnancy (Adrian, 1973).

MESORIDAZINE.

Mesoridazine, a piperidyl phenothiazine, is the major active metabolite of thioridazine and is an effective antipsychotic agent. No reports are published regarding the safety of its use during the first trimester. Phenothiazines that have been studied appear to be safe to use during gestation. Mesoridazine was given to pregnant rats and rabbits in doses 12 times those used in humans and no increased frequency of congenital anomalies among the offspring was found (Van Ryzin et al et al., 1971).

PERPHEn.a.z.iNE.

Perphen.a.z.ine is a piperazine phenothiazine tranquilizer used to treat psychoses, and in lower doses helps control nausea and vomiting. Among the infants of 63 pregnant women who received perphen.a.z.ine during the first trimester, the frequency of congenital anomalies was not increased (Heinonen et al et al., 1977). In an unpublished study of 140 infants exposed to this drug during the first trimester, the frequency of congenital anomalies was not increased above the expected rate in the general population (Rosa, personal communication, cited in Briggs et al et al., 2004).

An increased frequency of chromosomal abnormalities (breaks and rearrangements) in peripheral blood lymphocytes in patients taking perphen.a.z.ine was found in one study (Nielen et al et al., 1969), but the relevance of this to gametic chromosomes is unknown. No reports examining the effects of somatic chromosomal breaks on the gametes or children of these patients have been published. Typically, somatic chromosomes are not conserved because they have no genetic progeny. Only breaks in gametic chromosomes are directly relevant to reproduction or genetic toxicity. Offspring of pregnant rats treated with perphen.a.z.ine had an increased frequency of cleft palate and micromelia (Beall, 1972; Druga, 1976). Suppression of the mother's appet.i.te was thought to play a causative role in the cleft palate teratogenic effect (Szabo and Brent, 1974, 1975).

THIORIDAZINE.

Thioridazine is one of the most frequently used phenothiazine tranquilizers and is the prototype piperidine compound. Thioridazine is used to treat psychoses, emotional disorders, and severe behavioral problems. A small series of 23 newborns exposed to this medication during the first trimester was reported and no congenital defects were found (Scanlon, 1972). Offspring of mice and rats were given this phenothiazine in doses greater than those used in humans during embryogenesis; an increased frequency of cleft palate was observed (Szabo and Brent, 1974). Frequency of cleft palate was not Antipsychotics Antipsychotics 193.

increased in frequency when pregnant mice and rats were given forced feedings (Szabo and Brent, 1975).

THIOTHIXENE.

Thiothixene is a thioxanthine tranquilizer used to treat psychosis. Chemical structure and pharmacological activity of thiothixene are similar to the piperazine phenothiazine compounds. First-trimester exposure to thiothixene was not a.s.sociated with an increased frequency of congenital anomalies among 38 infants in one study (Rosa, personal communication, cited in Briggs et al et al., 2004). The frequency of congenital anomalies was not increased among offspring of pregnant mice or rabbits given 20180 times the typical human dose of thiothixene during embryogenesis (Owaki et al et al., 1969a, 1969b).

MOLINDONE.

Molindone is an indole derivative that is not related chemically to the phenothiazines, butyrophenones, or thioxanthenes, but is an effective antipsychotic drug. No studies have been published of birth defects in newborns that were exposed to molindone in in utero utero, and no studies in animals evaluating its teratogenic effects are available.

LITHIUM SALTS AND BIPOLAR TREATMENT.

Bipolar disorder is treated with mood stabilizers (lithium, anticonvulsants, antipsychotics) with an adjuvant antidepressant if necessary. Lithium is effective in the prophylaxis and treatment of affective psychiatric disorders.

Of all the psychotropic agents currently available, lithium has received the greatest attention as a possible teratogen. Cardiovascular system anomalies, particularly Ebstein's anomaly, have been reported to be increased among the infants of mothers that received lithium carbonate during the first trimester (Nora et al et al., 1974), but the question of the magnitude of these risks has been questioned (Cohen et al et al., 1994). Ebstein's anomaly is induced between weeks 2 and 6 postconception.

Three congenital anomalies were reported among 60 infants exposed to lithium in in utero utero. This is no different from the incidence in the general population (Schou and Amidsen, 1971). Among 50 women who reportedly received lithium during gestation, one infant had myelomeningocele, one had unilateral hernia, and none had congenital heart defects (Cunniff et al et al., 1989). No maternal history of lithium ingestion was found among 40 infants with Ebstein's anomaly and in 44 with tricuspid atresia (Kallen, 1971).

The risk of Ebstein's anomaly and other birth defects was reevaluated, and the risk of cardiac anomalies appears to be much less than estimated in previous studies (Cohen et al et al., 1994; Miller, 1994a, 1996). The early recommendation that women who take lithium salts during early gestation should undergo prenatal diagnosis with fetal echocardiography (Allan et al et al., 1982) is still valid (Yonkers et al et al., 2004). The risk of birth defects a.s.sociated with lithium was probably overestimated in the past (Yonkers et al et al., 2004). The risk is 'likely to be weak if it exists' and the 'data certainly do not support the 30-fold increased risk of Ebstein's anomaly suggested by the Register of Lithium Babies' (Moore, 1995). Nonetheless, first-trimester exposure to lithium is an indication for a fetal echocardiogram, targeting the competence and function of the tricuspid valve.

194.

Psychotropic use during pregnancy Table 10.3 Lithium exposure during first trimester and congenital anomalies Exposed Non-heart Heart Lithium exposure during first trimester and congenital anomalies Exposed Non-heart Heart Ebstein's anomalies anomalies anomaly N.

n/N %.

n/N %.

n/N %.

Cohort studies Background 35/1000 3.5.

8/1000 0.8.

1/20 000 0.005.

Weinstein (1980) 225.

7/225.

3.1.

18/225 8.0.

6/225.

2.7.

Jacobsen et al. (1992) 138.

3/138.

2.2.

0/138.

0.

1/138a 0.8.

Kallen and Tandberg 59.11/59.

18.6.

4/59.

6.8.

0/59.

0.

(1983).

Ebstein's anomaly Unaffected control Lithium exposure Lithium exposure Yes No Yes No Casecontrol studies Kallen (1988) 69.0.

128.

0.

Edmonds and Oakley 34.0.

34.0.

(1990).

Zalzstein et al. (1990) 59.0.

168.

0.

Correa-Villasenor et al. 44 0.

3572.

0.

(1994).

aThe case of Ebstein's anomaly was a therapeutic abortion.

Adapted from Yonkers et al., 1998.

No increase in physical or mental anomalies was found in a follow-up study of 60 school-aged children that were exposed to lithium in utero in utero (Schou, 1976) (Schou, 1976) . . Lithium toxicity, including cardiac, hepatic, and neurological abnormalities, has been reported in newborns of mothers who took lithium salts at term (Morrell Lithium toxicity, including cardiac, hepatic, and neurological abnormalities, has been reported in newborns of mothers who took lithium salts at term (Morrell et al et al., 1983; Woody et al et al., 1971). Diabetes insipidus and polyhydramnios are also complications attendant to lithium-exposed pregnancies.