Part 22 (2/2)

Oxazepam and clonazepam are benzodiazepine tranquilizers. Among 89 infants born to women who used oxazepam during the first trimester, there were no congenital anomalies (Ornoy et al et al., 1998). Small numbers of first-trimester exposure to clonazepam are published in clinical case series, but they are confounded by concomitant use of other known teratogens (anticonvulsants), as well as small sample sizes and sample selection bias (Friedman and Polifka, 2006).

Congenital anomalies were not increased in frequency among the offspring of pregnant rabbits or rats administered oxazepam in doses greater than those used in humans (Owen et al et al., 1970; Saito et al et al., 1984). Changes in behavior were observed among the offspring of pregnant mice given oxazepam in doses four to 42 times those used clinically (Alleva and Bignami, 1986).

MISCELLANEOUS.

Hydroxyzine Hydroxyzine is a piperazine antihistaminic compound that is used to treat anxiety, pruritus, nausea, and vomiting. The frequency of congenital anomalies in a double-blind controlled study was not increased among 74 newborns exposed in utero in utero to hydroxyzine (50 mg/day) during the first trimester (Erez to hydroxyzine (50 mg/day) during the first trimester (Erez et al et al., 1971). Birth defects were not increased in frequency among 50 infants born to women who used hydroxyzine during the first trimester (Heinonen et al et al., 1977). Hydroxyzine has been shown to be a teratogen in rats (Giurgea and Puigdevall, 1968; King and Howell, 1966).

Chloral hydrate Chloral hydrate is an effective hypnotic and sedative agent. There is a paucity of information regarding the safety of chloral hydrate use during pregnancy. However, among Miscellaneous Miscellaneous 201.

71 infants born to women who used chloral hydrate during the first trimester, the frequency of congenital anomalies was not increased (Heinonen et al et al., 1977). No gross external defects were observed in pregnant mice with chloral hydrate in doses less than one to five times the human dose (Kallman et al et al., 1984).

Ethchlorvynol Ethchlorvynol is a tertiary acetylenic alcohol and is used as an oral hypnotic and sedative agent. No studies have been published regarding the frequency of congenital malformations among newborns of women exposed to ethchlorvynol during gestation.

Symptoms of neonatal withdrawal were observed in the newborn of a woman who was treated with ethchlorvynol as a hypnotic during the last 3 months of gestation. Neonatal withdrawal symptoms observed were jitteriness, irritability, and hypotonia (Rumak and Walravens, 1973). No animal studies evaluating the teratogenic effects of ethchlorvynol are published, but behavioral changes were observed among the offspring of pregnant rats treated with ethchlorvynol in doses greater than those used in humans (Peters and Hudson, 1981).

Meprobamate Meprobamate is a carbamate tranquilizer that is useful in the treatment of anxiety but seems to be less effective than the benzodiazepines. The most common side effect is drowsiness. Inconsistencies in studies of the possible teratogenic effects of meprobamate in humans make it difficult to a.s.sess the risk of congenital anomalies with exposure to the drug in therapeutic doses during embryogenesis. Reports of an a.s.sociation between maternal use of this drug during the first trimester of pregnancy and a variety of congenital defects in newborns have been published, but the a.s.sociation is weak, and in no two studies was the same defect present. Among 66 infants born to women exposed to meprobamate in the first 42 days after their last menstrual period, congenital anomalies were increased fourfold (Milkovich and van den Berg, 1974). No apparent pattern of congenital anomalies was identified, but there were five infants with congenital heart disease. The frequency of hypospadias was increased among the 186 male infants born to women treated with meprobamate during the first trimester of pregnancy (Heinonen et et al al., 1977), but the finding was disregarded because of the small sample size. Accordingly, the relations.h.i.+p is probably a random finding, not representing a causal link. A third study had an increased frequency of major congenital anomalies among the newborns of more than 50 pregnant women given meprobamate during the first trimester (Jick et al et al., 1981), but no other details are available. Other studies have failed to find an a.s.sociation between the first-trimester use of meprobamate and congenital malformations. Among 356 pregnant women given meprobamate during the first trimester, the frequency of congenital anomalies was not increased (Heinonen et al et al., 1977). Another cohort study of congenital anomalies among 207 infants whose mothers used meprobamate during the first trimester failed to find an a.s.sociation (Belafsky et al et al., 1969). However, it should be noted that these studies a.n.a.lyzed only therapeutic dose exposures for infants examined for birth defects.

202.

Psychotropic use during pregnancy Table 10.4 Teratogen Information System (TERIS) and Food and Drug Administration (FDA) pregnancy risk ratings Teratogen Information System (TERIS) and Food and Drug Administration (FDA) pregnancy risk ratings Drugs TERIS risk FDA Pregnancy risk rating Alprazolam Unlikely Dm Amitriptyline Unlikely Cm Amobarbital None to minimal D*

Amoxapine Undetermined Cm Aprobarbital Undetermined C.

Bupropion Undetermined Bm Butalbital Unlikely C*

Chloral hydrate Unlikely Cm Chlordiazepoxide Unlikely D.

Chlorpromazine Unlikely C.

Clomipramine Unlikely Cm Clonazepam Undetermined Dm Clozapine Undetermined Bm Desipramine Undetermined C.

Diazepam Minimal D.

Doxepin Undetermined C.

Ethchlorvynol Undetermined Cm Fluoxetine Unlikely Cm Fluphen.a.z.ine Unlikely C.

Haloperidol Unlikely Cm Hydroxyzine Unlikely C.

Imipramine Unlikely D.

Isocarboxazid Undetermined C.

Lithium Small D.

Lorazepam Undetermined Dm Loxapine Unlikely C.

Maprotiline Undetermined Bm Mephobarbital Unlikely Dm Meprobamate Minimal D.

Mesoridazine Undetermined C.

Molindone Undetermined C.

Nortriptyline Undetermined D.

Oxazepam Unlikely D.

Pentobarbital Unlikely Dm Perphen.a.z.ine Unlikely C.

Phenelzine Undetermined C.

Phen.o.barbital Chronic anticonvulsive D.

Phenytoin/fosphenytoin Small to moderate D.

Protriptyline Undetermined C.

Secobarbital None Dm Sertraline Unlikely Bm Thioridazine Unlikely C.

Thiothixene Undetermined C.

Tranylcypromine Undetermined C.

Trazodone Unlikely Cm Trifluoperazine Unlikely C.

Compiled from: Friedman et al., Obstet Gynecol 1990; 75 75: 594; Briggs et al., 2005; Friedman and Polifka, 2006.

Miscellaneous 203.

The frequency of birth defects was not increased among the offspring of pregnant mice, rats, or rabbits given meprobamate in doses greater than those used in humans (range 2.516 times) (Brar, 1969; Clavert, 1963; Werboff and Dembicki, 1962). In other studies when doses 16 times greater than those used in humans were administered to rabbits, and doses 2.5 or 20 times the typical dose in humans were given to pregnant rats, fetal and neonatal loss was increased (Bertrand, 1960; Clavert, 1963; Werboff and Kesner, 1963).

Methaqualone Methaqualone (Quaalude, Sopor, Parest) is an effective hypnotic and sedative agent and is not presently commercially available. No clear medicinal advantage of methaqualone over the other available hypnotics can be shown and the drug is commonly abused by drug-dependent people. Tolerance to the drug develops in abusers. No published reports are available that a.n.a.lyze the possible a.s.sociation of the use of methaqualone during pregnancy with congenital malformations. However, its use during gestation is not recommended because of its abuse potential. The frequency of congenital anomalies was not increased among rats or rabbits whose mothers were administered 200 mg/kg methaqualone orally (rabbits) from days 1 to 29 or 100 mg/kg (rats) from days 1 to 20 (Bough et al et al., 1963) (Table 10.4).

Electroconvulsive therapy High-voltage electrical shock is used to treat some psychiatric disorders, although it may also occur in accidental electrocution. The mechanism of action of electroconvulsive therapy is unknown. However, it is clearly understood that the seizure produced by electroconvulsive therapy is necessary for therapeutic efficacy (Ottosson, 1962a, 1962b). Electroconvulsive therapy was used safely in the treatment of depression in a pregnant woman following expanded clinical guidelines that included the presence of an obstetrician during treatment, endotracheal intubation, low-voltage, nondominant therapy with electrocardiographic and electroencephalogram monitoring, Doppler ultrasonography of fetal heart rate, tocodynamometer recording of uterine tone, arterial blood gases during and after treatment, glycopyrrolate (anticholinergic of choice) use during anesthesia, and weekly nonstress tests (Wise et al et al., 1984). The frequency of birth defects among the newborns of 318 women who received electroconvulsive therapy during gestation has not increased (Impastato et al et al., 1964).

Reports of uterine contractions, v.a.g.i.n.al bleeding, and transient benign fetal cardiac arrhythmias have been published (Miller, 1994b; Rabheru, 2001). Miscarriage was reported following a third electroconvulsive therapy session in the first trimester of pregnancy (Moreno et al et al., 1998). One infant was described with hydrops fetalis and meconium peritonitis after the mother received electroconvulsive therapy during the third trimester of pregnancy (Gilot et al et al., 1999). As is usually the case with isolated reports, it is not possible to evaluate any causal links with anecdotal data.

No animal studies evaluating the teratogenic effects of high-voltage electrical shock have been published.

204.

Psychotropic use during pregnancy SPECIFIC CONDITIONS.

Depression Management of depression during pregnancy should be undertaken in consultation with a psychiatrist and/or psychologist (Yonkers, 2003). Although psychotherapy or hospitalization in a supportive environment is the first consideration in treatment (Spinelli, 2001; Yolles, 2001), antidepressant therapy may be necessary if these regimens are unsuccessful (Yolles, 2001; Robinson et al et al., 1986). Indeed, antidepressant medications are indicated in the pregnant woman whose depression is so severe that it threatens her life and the life of her unborn child (Yolles, 2001; Yonkers 2003). Since the medications used in the treatment of depression have potential fetal risks and may result in obstetric complications and long-lasting sequelae, the minimal effective antidepressant dose should be initiated and maintained. Most antidepressants have established therapeutic serum levels that can be monitored.

No antidepressant has proven safety for use during gestation, although some are better studied than others. Thus the selection of an antidepressant is dependent upon a patient's past response, side effects, and potential teratogenic effects of the particular agent. However, it is recommended that one uses an agent that has been relatively well studied during pregnancy and that has relatively few side effects (Miller, 1994a, 1996).

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