Journal of Psychiatric Practice:
Winner of Resident Paper Award 2004-2005
Psychotropic Drugs in Pregnancy and Lactation
JAIN, AUDREY E. DO; LACY, TIMOTHY MD
JAIN: Walter Reed Army Medical Center; LACY: Malcolm Grow Medical Center.
Please send correspondence and reprint requests to: Audrey E. Jain, DO, Walter Reed Army Medical Center, Department of Psychiatry, 6900 Georgia Avenue NW, Washington, DC 20307-5001.
The management of psychotropic medications during pregnancy and lactation involves a difficult and complex decision for both patient and provider, particularly due to the many unknown effects medication may have on the infant. Available studies concerning use of psychotropic medications in pregnant and lactating women are limited and there are no universal guidelines. This article reviews the literature on the use of psychotropic drugs, including antidepressants, mood stabilizers, antipsychotics, and benzodiazepines, in pregnant and breast-feeding women and presents relevant data on teratogenic effects, neonatal toxicity, perinatal syndromes, and neurobehavioral sequelae.
More than 500,000 pregnancies each year involve women who have psychiatric illnesses that predate or emerge during pregnancy.1 Many of these women will need medications sometime during or after pregnancy. Thirteen percent of psychiatric admissions for women occur during the first postpartum year.2 Up to 70% of pregnant women may endorse depressive symptoms, with 10%-16% of pregnant women fulfilling diagnostic criteria for major or minor depression.3 Psychotic disorders have also been observed to worsen during pregnancy.4 Of women with obsessive-compulsive disorder, 15%-39% report onset of symptoms during pregnancy.5,6 Treatment of these illnesses may require the use of psychotropic medications, but treatment should be selected on an individual basis after both patient and clinician weigh risks, benefits, and uncertainties of using medications during pregnancy and lactation.
The primary concerns regarding use of psychotropic medications during pregnancy and lactation include physical or neurobehavioral teratogenesis in the fetus, neonatal toxicity, and neonatal withdrawal.7 In the general population of the United States, 2%-4% of infants have malformations that impair function and/or require surgical correction.8 Medication use during the first trimester of pregnancy is the time period of concern regarding physical teratogenesis. It is during this embryonic period (third through eighth week of gestation) that most organs develop.7 During the first several cell divisions, the developing embryo is thought to be protected against the effects of drugs because the placenta is not yet being formed. The period of protection is between conception (day 14) and the first missed period (approximately day 28).9
Research on psychotropic medications during pregnancy has produced limited results due to inadequate sample sizes, reliance on case reports, questionable controls, and difficulty controlling for confounding variables such as diagnosis, maternal age, use of alcohol and other substances, smoking, gravidity history, previous pregnancy loss, genetic history, and timing of drug exposure.7,10 A diverse conglomeration of sources makes up the pregnancy and lactation reproductive safety data base for psychotropic medications; these sources include isolated case reports, case series from pharmacological companies and academic centers, birth registries, retrospective surveys, reports from teratology and poison control centers, review articles, the American Academy of Pediatrics (AAP) breast-feeding rating system, and the U.S. Food and Drug Administration (FDA) pregnancy rating system.7 Tables 1 and 2 show the FDA pregnancy risk categories for medications11 and the AAP breast-feeding scale.11,12 The AAP has a very conservative approach to recommending medications during lactation. The FDA Use-in-Pregnancy scale is letter based; it does not specify the adverse risks involved and is limited in its helpfulness to clinicians. The FDA is considering revamping the current system. Since 1997, the FDA task force has been looking at replacing the letter categories with more narrative descriptions providing information related to fertility, pregnancy, and breast-feeding. The FDA has not approved any psychotropic medication for use during pregnancy or lactation,7 so that it is up to the provider and patient to individually weigh the risks and benefits of medication use (Table 1). Table 3 (p. 188) presents a summary of information on psychotropic medications discussed in this article.
It can be a difficult challenge to determine the correct therapeutic dose of medication during pregnancy and the postpartum period because of the dynamic changes pregnancy produces in a woman's body. Pregnancy alters the pharmacokinetics (absorption, metabolism, distribution, and elimination) of psychotropic medications, producing effects such as decreased gastric acid and gastrointestinal emptying (drug absorption),13 increased extracellular fluid volume and body fat (drug distribution), changes in intrahepatic (P450 system) and extra-hepatic activity (drug metabolism),14 and increased glomerular filtration rate and renal blood flow (drug elimination).15 Due to these pharmacokinetic changes, clinicians should closely monitor patients, particularly during the third trimester and the antepartum period, to ensure adequate dosing of the medication.
Many physiologic changes occur in neonates after birth, including a highly variable hepatic maturation rate. Hepatic enzymes generally develop by 3 months of age.16 This makes the infant particularly vulnerable to the hepatotoxic effects of psychotropics given at the end of pregnancy and during breast-feeding in the first few months after birth. Close observation of the infant for jaundice or other signs of toxicity is recommended.
Women on medication who choose to breast-feed should be properly educated concerning signs of medication toxicity. Formula supplements should be used during any periods of infant illness or dehydration. Lactation studies use a milk-to-plasma ratio to calculate the daily dose the infant receives during breast-feeding. It is recommended that the infant's dose exposure be no more than 10% of the average maternal plasma level.17
Selective Serotonin Reuptake Inhibitors
The selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine, are a medication class that has been well studied in pregnancy and lactation.7 Multiple studies have shown no teratogenic effects with exposure any time during pregnancy to fluoxetine,18,19 fluvoxamine, paroxetine, and sertraline.20 Nevertheless, SSRIs may cause certain clinical problems. Gestational exposure to SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline) late in pregnancy has been found to be associated with an increase in premature delivery, lower birth weight, and lower APGAR scores.21 Exposure to fluoxetine during the third trimester has been reported to be associated with a higher risk for perinatal complications22 and a higher frequency of newborn admissions to special care nurseries compared with first trimester exposure to fluoxetine (18.9% vs. 9.1%).23 Adverse events in neonates associated with third trimester exposure to paroxetine included neonatal symptoms of irritability, jitteriness, constant crying, shivering, eating or sleeping difficulties, gastrointestinal symptoms, and seizures.24-27 In a prospective study, paroxetine was associated with a higher rate of neonatal complications (12/55 patients) including respiratory distress (9/55), hypoglycemia (2/55), and jaundice (1/55), all of which resolved within 1 to 2 weeks.25 Fortunately, most prospective studies have not demonstrated significant adverse effects in infants exposed to SSRIs with longer half lives than paroxetine,20,23,28-30 although case reports indicate that fluoxetine may cause feeding problems and jitteriness.31 Monitoring of fetal to maternal ratios of umbilical cord concentrations of fluoxetine, paroxetine, citalopram, and sertraline showed considerable differences in the medication ratios, suggesting that sertraline produces the least medication exposure to the fetus while fluoxetine and citalopram produce the most fetal medication exposure.32 No studies are available on escitalopram.
A prospective study by Nulman et al. of children aged 15-71 months exposed in utero to either SSRIs or tricyclic antidepressants (TCAs) showed no apparent neurobehavioral effects with prenatal exposure to either fluoxetine or TCAs in IQ, temperament, behavior, reactivity, language, mood, or distractibility.30,33
Long-term neurobehavioral studies of infants exposed to antidepressants during lactation have not been conducted.7. A pooled analysis of 57 studies on antidepressants and breast-feeding indicated that nortriptyline, paroxetine, and sertraline produce undetectable levels of these drugs in infants, while fluoxetine produced the highest proportion (22%) of infant levels elevated above 10% of the average maternal level.34 This study indicated that nortriptyline, paroxetine, and sertraline may be the preferred choices among the SSRIs for use during lactation due to their lower infant-to-maternal ratio.
TCAs have been available in the United States since 1963 without clear associations between TCA exposure and congenital malformations.7,8 Desipramine (a secondary TCA) is the preferred TCA because it is less anticholinergic and least likely to cause orthostatic hypotension during pregnancy.35 Amitriptyline, imipramine, and nortriptyline have received FDA D ratings. Early studies involving all TCAs were suggestive of limb anomalies.36,37 However, a recent meta-analysis of TCAs representing over 300,000 live births did not identify an increase in congenital malformations of infants exposed to any TCA during the first trimester of pregnancy.13 The dose of TCAs may need to be increased up to 1.6 times the preconception dose to maintain a therapeutic concentration late in pregnancy.7 Anticholinergic effects can cause neonatal toxicity, including symptoms of functional bowel obstruction and urinary retention.38,39 TCA withdrawal in neonates has been observed with symptoms of jitteriness, irritability, and, less commonly, seizures,40-44 although such withdrawal seizures have only been reported with clomipramine.40,44 In all these cases, the symptoms have been transient. The landmark neurodevelopmental study of TCAs and SSRIs by Nulman et al. (see previous section for findings concerning SSRIs) showed no neurobehavioral effects compared with control infants aged 15-71 months.30,33 TCAs have been widely used during lactation.34 Doxepin should be avoided during lactation due to one case report of an infant with respiratory depression.45
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) have been used for more than 40 years with limited pregnancy data. Animal studies have reported teratogenic potential from embryonic exposure to MAOIs.46 Terbutaline sulfate, a drug used to forestall delivery, should be used with caution in combination with an MAOI due to the potential to cause an adrenergic crisis.11 Due to dietary and medication restrictions, along with the potential to cause hypertensive crises, this class should not be used during pregnancy.7
Other Antidepressants (Bupropion, Mirtazapine, Venlafaxine, Duloxetine)
Limited data exist regarding the use of other antidepressants during pregnancy and lactation.
Bupropion is classified as category B due to no adverse outcomes in animal studies.7 However, limited human data on use in pregnancy and lactation are available for bupropion. A recent prospective comparative study of 136 women exposed to bupropion during pregnancy did not show an increase in the rates of major malformations among infants.47
Data on venlafaxine are limited but a multicenter prospective controlled study suggests that first trimester use does not increase the teratogenic risk.48 With regard to lactation, the mean total infant dose was 7.6% (range 4.7%-9.2%) of the maternal weight-adjusted dose.49 It is recommended that breast-fed infants of mothers taking venlafaxine be closely observed.49
At this time, there are no published data on duloxetine in pregnancy or lactation.
Limited data exist on mirtazapine. Animals receiving 17-20 times the maximum recommended human dose of mirtazapine (based on mg/m2) did not show teratogenic effects, but did have an increase in pup death and a decrease in the birth weight.11 A recent comparative meta-analysis of mothers who took newer antidepressants during the first trimester of pregnancy (N = 1774) did not show higher rates of major malformations in infants of mothers exposed to these antidepressants compared with infants of nonexposed mothers.50 The antidepressants examined included mirtazapine, along with citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, reboxetine, venlafaxine, nefazodone, trazodone, and bupropion. Lactation studies for mirtazapine are limited to a case report of a breast-fed infant who did not show adverse effects.51
Consensus Guidelines on Depression in Women
An excellent source for clinicians faced with selecting treatment options (medication and non-medication strategies) for depressed patients trying to conceive, during pregnancy, and through the postpartum period is the 2001 Expert Consensus Guidelines on the Treatment of Depression in Women.52,53 The purpose of the guidelines is to provide guidance where research data are lacking based on a survey of expert opinion.
Lithium's teratogenicity has been overestimated in the past.54 Previous studies indicated a 400-fold increase in congenital heart malformations, particularly Ebstein's anomaly.55 Subsequent investigations have indicated that the risk of Ebstein's anomaly with lithium treatment is 20-40 times higher than the rate in the general population, in which the rate of Ebstein's anomaly is 1/20,000.56-58 Although lithium does present these risks for adverse effects, the risks are significantly lower than previously believed.
Lithium has been known to cause "floppy baby syndrome," characterized by cyanosis and hypotonia.59,60 Case reports concerning late gestational exposure describe fetal cardiac arrythmias,61 hypoglycemia, nephrogenic diabetes insipidus,59 reversible thyroid changes,62 polyhydraminos,63 infants large for gestational age,64 flaccidity, lethargy, and poor sucking reflex.65 A 5-year follow-up of 60 school-age children exposed to lithium during gestation found no overt evidence of neurobehavioral changes.66 Lithium levels in the umbilical cord have been found to be equivalent to maternal blood levels.67
No reports regarding long-term neurobehavioral sequelae of lithium exposure during lactation exist. The AAP12 discourages the use of lithium during lactation and suggests breast-feeding should be undertaken with caution due to lithium infant toxicity.7 Two issues regarding breast-feeding during lithium treatment include concern about rapid dehydration in neonates7 and diminished renal clearance, both of which can elevate lithium levels.67
Lithium should be tapered prior to conception in patients with mild illnesses; in more severe cases, patients should be counseled either to avoid lithium during the first trimester or use the lowest amount possible in divided doses.7 Lithium recommendations also include a fetal echocardiogram with high resolution8,57 ultrasound between 16 to 18 weeks gestation, a neonatal electrocardiogram, and monitoring of the infant for 10 days after birth for lithium toxicity.64 Lithium levels should be monitored weekly in the last month of pregnancy.64 In the third trimester, renal excretion may increase by 30% to 50%, requiring an increase in the lithium dose.68 Therefore, to avoid neonatal toxicity, it is recommended to either discontinue lithium 2-3 days before delivery or decrease the dose by 25%.57,69-71
Valproic acid (VPA) is considered a teratogen and is associated with numerous malformations including neural tube defects with a prevalence 10-20 times greater than in the general population;72-74 craniofacial anomalies,75 limb abnormalities,76 cardiovascular anomalies,77-79 genitourinary malformations,80 and low birth weight.81,82 The risk of fetal malformations increases with anticonvulsant polypharmacy and in mothers who exceed 1000 mg VPA per day.7 Symptoms of fetal valproate syndrome include epicanthal folds, flat nasal bridges, small nose with anteverted nostrils, long upper lip with shallow philtrum, small mouth with downturned angles, micrognathia, and a thin upper vermillion.76,83-85 Infant toxicity includes hepatotoxicity,86 coagulopathies,87 and neonatal hypoglycemia.88
VPA concentrations in the mother have been found to be 50% lower in the final month of pregnancy compared with levels earlier in the pregnancy89 and this may require an increase in the dosage. Fetal concentrations were 145%-219% higher than maternal levels at delivery.89-91 If used during pregnancy, folate supplements should be given due to the antagonistic effect of VPA on folate and the association between neural tube defects and folate deficiency.7 While a matter of some controversy, pre-conception folate may help prevent these defects.
Most neurobehavioral studies on VPA have been done in women with epilepsy, so that it is difficult to discriminate the effects of prenatal anticonvulsant exposure from prenatal exposure to maternal epilepsy.7 Retrospective reports indicate developmental delay and mental retardation in children exposed to VPA monotherapy prenatally.84,92,93
Lactation appears to be safe in mothers maintained on VPA. The American Academy of Neurology advocates breast-feeding while on VPA.94 Serum concentrations in infants vary from 4%-40% of maternal levels. No adverse effects have been reported in infants whose mothers were solely on VPA during lactation.7,95
Carbamazepine (CBZ) has teratogenic risks similar to VPA, but these are less frequent and severe.7 Teratogenic effects include neural tube defects,96,97 cleft palate, cardiovascular abnormalities, and urinary tract anomalies.98 Fetal carbamazepine syndrome is manifested by a short nose, long philtrum, epicanthal folds, hypertelorism, upslanting palpebral fissures, and fingernail hypoplasia.97 CBZ's teratogenic potential is increased when it is given in combination with VPA.99 Maternal serum alpha fetoprotein levels, fetal echocardiogram and level 2 ultrasound at 16-18 weeks gestation, and folate supplementation (4-5 mg per day) are recommended.7 CBZ has been linked to reductions in birth weight (approx 250 gm)100 decreased mean head circumference,101 transient hepatic toxicity,102 and fetal vitamin K deficiency. Oral vitamin K (20 mg/day) is therefore recommended in the last month of pregnancy, and the infant should receive 1 mg IM of vitamin K after in utero CBZ exposure.54 Fetal serum levels of CBZ have been shown to be 50%-80% of maternal levels.103 CBZ is not recommended unless other options are lacking during gestation. Neurobehavioral studies include a prospective controlled study of 36 mother-child dyads in which there was in utero exposure to CBZ which found no significant differences on neurobehavioral tests.104 The American Academy of Neurology advocates breast-feeding while on CBZ.7 The AAP committee on medications lists both VPA and CBZ as compatible with breast-feeding.105 The serum concentrations of CBZ in breast-feeding infants ranged from 6%-65% of maternal levels.106
Others Mood Stabilizing Agents (Lamotrigine/Oxcarbazepine)
Data on lamotrigine (LTG) and oxcarbazepine are limited and there are no neurobehavioral data.7 Oxcarbazepine has been used in Europe for more than a decade and retrospective studies on 12 patients with first trimester exposure107 have found no congenital anomalies. Folate supplementation should be given until the teratogenic risks are further clarified.7 A study of 12 deliveries indicated that fetal-maternal concentrations of oxcarbazepine were equal.108,109
The Lamotrigine Pregnancy Registry indicates less than a 2% risk for fetal malformation with first trimester exposure to LTG based on a total of 1081 registered cases and 693 obtained birth outcomes (as of Sept 2003).7,54 In animal studies, rats had decreased folate concentrations when exposed to LTG.110 Routine folate supplementation (4-5 mg/day) is recommended in women of reproductive age (pregnant or not).7 LTG clearance progressively increased (N = 14) until 32 weeks, when it reached a peak of > 330% of baseline and then began to decline.111 A series of small studies indicate that fetal LTG concentrations are equal to maternal levels at delivery.112,113 A follow-up study showed no developmental abnormalities in 12 month olds (N = 23) who were exposed to LMG during gestation.114
Findings concerning serum concentrations of LTG in nursing infants are inconclusive. LTG is metabolized exclusively by glucuronidation, and this process is undeveloped in the fetus and neonate. Thus LTG is not recommended for use during lactation.112
Literature on the following second-generation (atypical) antipsychotics was reviewed: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. All of these agents are FDA category C except clozapine, which is category B.7 Data on the safety of the second-generation antipsychotics in pregnancy and lactation are limited. A few studies have suggested that these agents may increase the risk of hyperglycemia in pregnant women.115 The results of a recent cohort of pregnant women (N = 151) exposed to second generation antipsychotics during pregnancy (olanzapine n = 60, risperidone n = 49, quetiapine n = 36, and clozapine n = 6) suggest that second-generation antipsychotics do not appear to be associated with an increased risk for major malformations.116
Clozapine is the oldest of the second-generation antipsychotics. Collective case reports, case series, and retrospective reviews involving 73 infants exposed during pregnancy and lactation117-121 have shown only one report of maternal gestational diabetes,121 (the authors noted that this was possibly exacerbated by clozapine and complicated management of the pregnancy, but the baby was healthy), and several reports of minor anomalies (cephalohematoma, hyperpigmentation folds, cocygeal dimple, and floppy infant syndrome).118 No cases of agranulocytosis have occurred in infants, but it is considered a theoretical risk. Newborns exposed in utero should have a CBC for leukocyte count evaluation.7 Clozapine levels in breast-fed infants have been found to be 432% of the mother's serum level on the day of delivery, and 279% 1 week after delivery.117 Case reports have indicated that nursing infants have experienced sedation, agranulocytosis, and cardiovascular instability.120,122 Clozapine should not be used during breast-feeding.7
In a prospective study of 23 pregnant women who received olanzapine at doses ranging from 5-25 mg, there were no reports of major congenital malformations.123 Two cases of gestational diabetes were reported in women without a family or personal history of glucose intolerance.123 In a prospective study of 96 women taking olanzapine during gestation, 71.9% had normal births and all results were within the range of normal controls.124 Among 21 reports of breast-fed infants exposed to olanzapine, 5 showed adverse effects including jaundice, cardiomegaly, and heart murmur, shaking, poor suckling, lethargy, protruding tongue, rash, diarrhea, and sleeping disorders.124,125 Lactation case studies have indicated that infant doses were 0.22%-2.5% of maternal daily dosage.126,127
Data on the safety of risperidone during pregnancy and lactation are limited. A report concerning two women who received risperidone during pregnancy and lactation showed no adverse effects in the infants.128 A single case of agenesis of the corpus callosum in an infant was reported during premarketing trials of gestational use by the mother.129 Lactation data (N = 4) have shown no adverse reactions.128,130
Quetiapine studies are limited to a case report that did not show adverse effects.131 Animal studies have shown some evidence of delays in skeletal ossification, reduced fetal weight, and increased fetal and pup death in preliminary animal studies.124 One case report of a lactating woman indicated infant exposure to be 0.43% of the maternal dose.132
There are no reports concerning use of ziprasidone and aripiprazole during pregnancy or lactation in humans. Animal studies on ziprasidone (at equivalent human doses) have shown developmental delay, possible teratogenic effects, and an increase in stillbirths.115 Animal studies on aripiprazole have demonstrated delayed skeletal ossification at 3-10 times the maximum recommended human dose, and decreased fetal weight.133
High-potency conventional antipsychotics (e.g., haloperidol) have not been found to have teratogenic effects,13 but low-potency antipsychotics (e.g., chlorpromazine) have a small but statistically significant increased risk for nonspecific teratogenic effects with first trimester exposure.134 A theoretical risk of neuroleptic malignant syndrome in the neonate exists with both high- and low-potency conventional antipsychotics.135 Prenatal exposure to conventional antipsychotics has been shown to cause extrapyramidal side effects manifested by heightened muscle tone, increased rooting and tendon reflexes (persisting for several months),136,137 neonatal jaundice, and postnatal intestinal obstruction.38 Neurobehavioral studies have shown no consistent findings. One study did not find any difference in IQ scores in 4-year-old children who were gestationally exposed to conventional antipsychotics.138 Two studies report deficits in behavior and development in rat offspring exposed prenatally to chlorpromazine.139,140 Lactation studies have uniformly reported milk to plasma ratios of less than one.7
Early studies of benzodiazepines (BZDs) indicated an increased risk of oral clefts after first trimester exposure to diazepam,141,142 but later studies failed to confirm this association.143-145 Prospective studies of the use of alprazolam during the first trimester in 1,300 women reported no increased incidence of oral clefts or congenital anomalies,146,147 and 445 infants in a case control study showed no increase in oral clefts in first trimester exposure to diazepam.144 A pooled meta-analysis found the risk of oral clefts, which is 6/10,000 in the general population, increased only 0.01% to 7/10,000 with first trimester exposure to BZDs.8 No controlled studies have been done on clonazepam.8 A recent meta-analysis that reviewed data from 1,400 studies showed no risk of major malformations based on cohort studies, but did find an association between BZD exposure and development of major malformations or oral cleft when case control studies were analyzed.148 Due to the conflicting data, it is recommended that BZDs be avoided during pregnancy, particularly in the first trimester, and that a level 2 ultrasound be obtained during pregnancy to rule out visible forms of oral cleft.148
BZDs have been shown to cause neonatal toxicity and withdrawal symptoms. Floppy infant syndrome includes hypothermia, lethargy, poor respiratory effort, and feeding difficulties after maternal use of BZDs.149-152 Neonatal withdrawal syndromes from alprazolam, chlordiazepoxide,153-155 and diazepam156 have been characterized by restlessness, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, and vomiting.146 These symptoms have been reported as long as 3 months after delivery.157 Animal studies have shown fetotoxic and embryotoxic effects, including death, intrauterine growth retardation, motor delays, and fetal weight gain.158 Fetal rates of benzodiazepine metabolism are considerably slower than in adults. The fetal-maternal ratio of diazepam is greater than 1 at delivery,159,160 and levels of lorazepam have been detectable in infants 8 days after delivery.161
No well conducted studies of the long-term neurobehavioral effects of intrauterine BZD exposure in infants have been performed. The existence of a "benzodiazepine exposure syndrome" is debatable. Symptoms in infants exposed prenatally to BZDs included growth retardation, dysmorphism, and both mental and psychomotor retardation.162 One study found no difference in the incidence of behavioral abnormalities at 8 months or in IQ scores at 4 years among children gestationally exposed to chlordiazepoxide.163 BZD studies in mice and rats indicated a reduction in BZD receptor density in the cortex and cerebellum without any alteration in the affinity of the receptors.164
Oxazepam has a 0.1-0.3 milk-to-plasma ratio, while fetuses whose mothers were taking lorazepam were exposed to 2.2% of the maternal doses.165 Neonates metabolize medications more slowly, potentially resulting in toxic serum levels. Thus, long-term use of BZDs by a breast-feeding mother could potentially lead to a buildup of the drug in the infant. If an infant experiences sedation or other signs of BZD toxicity, breast-feeding should be discontinued.7
Women who are taking psychotropic medications and are of reproductive age or are planning a pregnancy should understand the risks, benefits, and uncertainties of using such medications during pregnancy. If medications are needed during pregnancy, recommendations include waiting until after the first trimester when medications pose a teratogenic risk. If medications are needed, agents should be selected on the basis of existing data, ideally with a preference for monotherapy, and be prescribed at the lowest effective dose. Metabolism of medications may change during the course of pregnancy and after pregnancy. Clinicians need to be cognizant of these changes to help protect against both maternal and neonatal toxicities. Overall, the available research on the use of psychotropic medications during pregnancy and lactation is limited and involves many confounding variables and small sample sizes. Pregnant women need to be monitored more closely during and after delivery. Communication with other physicians, including the patient's obstetrician and pediatrician, is highly recommended.7 Women who choose to breast-feed while taking psychotropic medications should be educated about possible side effects and advised to discontinue the medication if their infant develops a toxic or adverse effect.
Table 3 summarizes the information on psychotropic medications discussed above and highlights key issues to consider prior to administering different medications during pregnancy and lactation.
1. Levey L, Ragan K, Hower-Hartley A, et al. Psychiatric disorders in pregnancy. Neurol Clin 2004;22:863-93.
2. Duffy CL. Postpartum depression: Identifying women at risk. Genesis 1983;11:21.
3. O'Hara MW, Neunabar DJ, Zekoski EM. Prospective study of postpartum depression: Prevalence, course, and predictive factors. J Abnorm Psychol 1984;93:158-71.
4. McNeil TF, Kaij L, Malmquist-Larson A. Women with nonorganic psychosis: Pregnancy's effect on mental health during pregnancy. Acta Psychiatr Scand 1984;70:127-39.
5. Neziroglu FN, Anemone MA, Yaryura-Tobias JA. Onset of obsessive-compulsive disorder in pregnancy. Am J Psychiatry 1992;149:947-50.
6. Williams KE, Koran L. Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstrum. J Clin Psychiatry 1997;58:330-4.
7. Newport DJ, Fisher A, Graybeal S, et al. Psychopharmacology during pregnancy and lactation. In: Schatzberg AF, Nemeroff CB. APA textbook of psychopharmacology, 3rd edition. Washington, DC: American Psychiatric Press; 2004:1109-46.
8. Altshuler LL, Cohen LS, Szuba MP, et al. Pharmacologic management of psychiatric illness in pregnancy: Dilemmas and guidelines. Am J Psychiatry 1996;153:592-606.
9. Cohen LS, Heller VL, Rosenbaum JF. Treatment guidelines for psychotropic drug use during pregnancy. Psychosomatics 1989;30:25-33.
10. Miller, LJ. Psychiatric disorders during pregnancy. In: Stotland, NL, Steward, DE. Psychological aspects of women's health care: The interface between psychiatry and obstetrics and gynecology, 2nd edition. Washington, DC: American Psychiatric Press; 2001:67-93.
12. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
13. Ward RK, Zamorski MA. Benefits and risks of psychiatric medications during pregnancy. Am Fam Physician 2002;66: 629-36.
14. Robson, SC Mutch E, Boy RJ, et al. Apparent liver blood flow during pregnancy: A serial study using indicyanine green clearance. Br J Obstet Gynaecol 1990;97:720-4.
15. Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. Br J Obstet Gynaecol 1974;81:588-95.
16. Warner A. Drug use in the neonate: Inter-relationships of pharmacokinetics, toxicity and biochemical maturity. Clin Chem 1986;32:721-7.
17. Cohen LS, Sichel DA, Robertson LM, et al. Postpartum prophylaxis for women with bipolar disorder. Am J Psychiatry 1995;152:1641-5.
18. Pastuszak A, Schick-Boschetto B, Zuber C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA 1993;269:2246-8.
19. Goldstein DJ, Corbin LA, Sundell, KL. Effects of first-trimester fluoxetine exposure on the newborn. Obstet Gynecol 1997;89(5 Pt 1):713-8.
20. Kulin N, Pastuszak A, Sage S, et al. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: A prospective controlled multicenter study. JAMA 1998;279:609-10.
21. Simon G, Cunningham M, Davis R. Outcomes of prenatal antidepressant exposure. Am J Psychiatry 2002;159:2055-61.
22. Chambers C, Johnson K, Dick L, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335: 1010-5.
23. Cohen L, Heller V, Bailey J, et al. Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry 2000;48: 996-1000.
24. Stiskal J, Kulin N, Koren G, et al. Neonatal paroxetine withdrawal syndrome. Arch Dis Child Fetal Neonatal Ed 2001;84:134-5.
25. Costei A, Kozer E, Ho T, et al. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 2002;156:1129-32.
26. Dahl M, Olhager E, Ahlner J. Paroxetine withdrawal syndrome in a neonate. Br J Psychiatry 1997;171:391-2.
27. Nordeng H, Lindemann R, Perminov K, et al. Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr 2001;90:288-91.
28. Goldstein DJ. Effects of third trimester fluoxetine exposure on the newborn. J Clin Psychopharmacol 1995;15:417-20.
29. Ericson A, Kallen B, Wiholm B. Delivery outcome after the use of antidepressants in early pregnancy. Eur J Clin Pharmacol 1999;55:503-8.
30. Nulman I, Rovet J, Stewart DE, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: A prospective, controlled study. Am J Psychiatry 2002;159:1889-95.
31. Spencer M. Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics 1993;92:721-2.
32. Hendrick V, Stowe Z, Alshuler L, et al. Placental passage of antidepressant medications. Am J Psychiatry 2003;160: 993-6.
33. Nulman I, Rovet J, Steward DE, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997;336:258-2.
34. Weissman A, Levy B, Hartz A, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk and nursing infants. Am J Psychiatry 2004;161:1066-78.
35. Nonacs R, Cohen L. Assessment and treatment of depression during pregnancy: An update. Psychiatr Clin North Am 2003;26:547-62.
36. Barston A. Malformed infants. Br Med J 1972;45:5804.
37. Elia J, Katz I, Simpson G. Teratogenicity of psychotherapeutic meds. Psychopharmacol Bull 1987;23:531-86.
38. Falterman CG, Richardson C. Small left colon syndrome associated with maternal ingestion of psychotropic drugs. J Pediatr 1980;97:308-10.
39. Shear W, Schreiner R, Marshall R. Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 1972;81:570-2.
40. Cowe L, Lloyd D, Dawling S. Neonatal convulsions caused by withdrawal from maternal clomipramine. BMJ 1982;284:1837-8.
41. Eggermont E. Withdrawal symptoms in neonates associated with maternal imipramine therapy. Lancet 1973;2:680.
42. Schimmel M, Katz E, Shaag Y, et al. Toxic neonatal effects following maternal clomipramine therapy. Clin Toxicol 1991;29:479-84.
43. Webster PAC. Withdrawal symptoms in neonates associated with maternal antidepressant therapy. Lancet 1973;2:318-9.
44. Bromiker R, Kaplan M. Apparent intrauterine fetal withdrawal from clomipramine hydrochloride. JAMA 1994;272: 1722-3.
45. Matheson I, Pande H, Alertson AR. Respiratory depression caused by N-desmethyldoxepine in breast milk. Lancet 1985;2:1124.
46. Poulson E, Robson J. Effect of phenelzine and some related compounds in pregnancy. J Endocrinol 1964;30:205-15.
47. Chun-Fai-Chan B, Koren G, Fayez I, et al. Pregnancy outcome of women exposed to bupropion during pregnancy: A prospective comparative study. Am J Obstet Gynecol 2005;192:932-6.
48. Einarson A, Fatoye B, Sarkar M, et al. Pregnancy outcome following gestational exposure to venlafaxine: A multicenter prospective controlled study. Am J Psychiatry 2001;158:1728-30.
49. Ilett K, Hackett LP, Dusci LJ, et al. Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human milk. Br J Clin Pharmacol 1998;45:459-62.
50. Einarson TR, Einarson A. Newer antidepressants in pregnancy and rate of major malformations: A meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf March 2005. (epub)
51. Aichhorn W, Whitworth AB, Weiss U, et al. Mirtazapine and breast-feeding. Am J Psychiatry 2004;161:2325.
52. Altshuler LL, Cohen LS, Moline ML, et al. The expert consensus guideline series: Treatment of depression in women 2001. Postgrad Med Special Report 2001(March):1-116.
53. Altshuler LL, Cohen LS, Moline ML, et al. Treatment of depression in women: A summary of the expert consensus guidelines. J Psychiatr Pract 2001;7:185-208.
54. Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161:608-20.
55. Weinstein M, Goldfield M. Cardiovascular malformations with lithium use during pregnancy. Am J Psychiatry 1975;132:529-31.
56. Edmonds L, Oaley G. Ebstein's anomaly and maternal lithium exposure during pregnancy. Teratology 1990;41:551-2.
57. Cohen L, Friedman J, Jefferson J, et al. A reevaluation of risk of in utero exposure to lithium. JAMA 1994;271:146-50.
58. Jacobsen S, Jones K, Johnson K, et al. Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 1992;339:530-3.
59. Mizrahi E, Hobbs J, Goldsmith D. Nephrogenic diabetes insipidus in transplacental lithium intoxication. J Pediatr 1979;94:493-5.
60. Nars P, Girard J. Lithium carbonate intake during pregnancy leading to large goiter in a premature infant. Am J Dis Child 1977;131:924-5.
61. Wilson N, Forfar J, Godman M. Atrial flutter in the newborn resulting from maternal lithium ingestion. Arch Dis Child 1983;58:538-49.
62. Karlsson K, Lindstedt G, Lundberg P. Transplacental lithium poisoning: Reversible inhibition of fetal thyroid (letter). Lancet 1975;1:1295.
63. Llewellyn A, Stowe Z, Strader J. The use of lithium and management of women with bipolar disorder during pregnancy and lactation. J Clin Psychiatry 1998;59(suppl 6):57-64.
64. Pinelli J, Symington A, Cunningham K, et al. Case report and review of the perinatal implications of maternal lithium use. Am J Obstet Gynecol 2002;187:245-9.
65. Woody J, London W, Wilbanks G. Lithium toxicity in a newborn. Pediatrics 1971;47:94-6.
66. Schou M. What happened later to the lithium babies? A follow up study of children born without malformations. Acta Psychiatr Scand 1976;54:193-7.
67. Schou M, Amdisen A, Steenstrup O. Lithium and pregnancy, hazards to women given lithium during pregnancy and delivery. BMJ 1973;2:137-8.
68. Schou M. Treating recurrent affective disorders during and after pregnancy. What can be taken safely? Drug Saf 1998; 18:143-52.
69. Austin M, Mitchell P. Psychotropic medications in pregnant women: Treatment dilemma. Med J Aust 1998;169:428-31.
70. Schou M. Lithium treatment during pregnancy, delivery, and lactation: An update. J Clin Psychiatry 1990;51:410-3.
71. Terp I, Mortensen P. Postpartum psychosis: Clinical diagnoses and relative risk of admission after parturition. Br J Psychiatry 1998;172:521-6.
72. Bjeredal T, Czeizel A, Goujard J, et al. Valproic acid and spina bifida (letter). Lancet 1982;2;1096.
73. Jager-Roman E, Deichl A, Jakob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986;108:997-1004.
74. Lindhout D, Schmidt D. In utero exposure to valproate and neural tube defects. Lancet 1986;1:329-33.
75. Paulson G, Paulson R. Teratogenic effects of anticonvulsants. Arch Neurol 1981;38:140-3.
76. Rodriguez-Pinilla E, Arroyo I, Fondevilla J, et al. Prenatal exposure to valproic acid during pregnancy and limb deficiencies: A case-control study. Am J Med Genet 2000;90: 376-81.
77. Dalens B, Raynaud E, Gaulme J. Teratogenicity of valproic acid. J Pediatr 1980;97:332-3.
78. Koch S, Jager-Roman E, Rating D, et al. Possible teratogenic effect of valproate during pregnancy. J Pediatr 1983;103:1007-8.
79. Sodhi P, Poddar B, Parmar V. Fatal cardiac malformations in fetal valproate syndrome. Indan J Pediatr 2001;68:989-90.
80. Adab N, Jacoby A, Smith D, et al. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2001;70:15-21.
81. Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 1982;2:937.
82. Martinez-Frias M, Rodriguez-Pinilla E. Salvador J. Valproate and spina bifida. Lancet 1989;1:611.
83. Di Liberti J, Farndon P, Dennis N, et al. The fetal valproate syndrome. Am J Med Genet 1984;19:473-81.
84. Martinez-Frias M. Clinical manifestation of prenatal exposure to valproic acid using case reports and epidemiologic information. Am J Med Genet 1990;37:277-82.
85. Winter R, Donnai D, Burn J, et al. Fetal valproate syndrome: Is there a recognizable phenotype? J Med Genet 1987;24: 692-5.
86. Kennedy D, Koren G. Valproic acid use in psychiatry: Issues in treating women of reproductive age. J Psychiatry Neurosci 1998;23:223-8.
87. Mountain K, Hirsh J, Gallus A. Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy. Lancet 1970;1(7641):265-8.
88. Ebbesen F, Joergensen A, Hoseth E, et al. Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate. Arch Dis Child Fetal Neonatal Ed 2000;83:F124-9.
89. Yerby MS, Friel PN, McCormick K, et al. Pharmacokinetics of anticonvulsants in pregnancy: Alterations in plasma protein binding. Epilepsy Res 1990;5:223-8.
90. Froescher W, Gugler R, Niesen M, et al. Protein binding of valproic acid in maternal and umbilical cord serum. Epilepsia 1984;25:244-9.
91. Philbert A, Pederson B, Dam M. Concentration of valproate during pregnancy in the newborn and in breast milk. Acta Neurol Scand 1985;72:460-3.
92. Moore S, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000;37:489-97.
93. Kozma C. Valproic acid embryopathy: Report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet 2001;98:168-75.
94. Holmes L, Harvey E, Coull B, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132-8.
95. Von Unruh G, Froescher W, Hoffmann AF, et al. Valproic acid in breast milk: How much is really there? Ther Drug Monit 1984;6:272-6.
96. Rosa F. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991;324:674-7.
97. Jones K, Lacro R, Johnson K, et al. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989;320:1661-6.
98. Matalon S, Schechtman S, Goldzweig G, et al. The teratogenic effect of carbamazepine: A meta-analysis of 1255 exposures. Reprod Toxicol 2002;16:9-17.
99. Lindhout D, Meinardi H, Meijer J, et al. Antiepileptic drugs and teratogenesis in two consecutive cohorts: Changes in prescription policy paralleled by changes in pattern of malformations. Neurology 1992;42:94-110.
100. Diav-Citrin O, Shechtman S, Arnon J, et al. Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies. Neurology 2001;57:321-4.
101. Hiilesmaa V, Teramo K, Granstrom M, et al. Fetal head growth retardation associated with maternal antiepileptic drugs. Lancet 1981;2:165-7.
102. Merlob P, Mor N, Litwin A. Transient hepatic dysfunction in an infant of an epileptic mother treated with carbamazepine during pregnancy and breast-feeding. Ann Pharmacother 1992;26:1563-5.
103. Nau H, Kuhnz W, Egger H, et al. Anticonvulsants during pregnancy and lactation: Transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet 1982;7: 508-43.
104. Scolnik D, Nulman I, Rovet J, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1994:271:767-70.
105. Gartner L. breast-feeding and the use of human milk. Pediatrics 1997;100:1035-9.
106. Chaudron L. Mood stabilizers during breast-feeding: A review. J Clin Psychiatry 2000;61:79-90.
107. Friis M, Kristensen O, Boas J, et al. Therapeutic experiences with 947 epileptic outpatients in oxcarbazepine treatment. Acta Neurol Scand 1993;87:224-7.
108. Myllynen P, Pienimai P, Jouppila P, et al. Transplacental passage of oxcarbazepine and its metabolites in vivo. Epilepsia 2001;42:1482-5.
109. Kalis M, Huff N. Oxcarbazepine, an epileptic agent. Clin Ther 2001;23:680-700.
110. Tennis P, Eldridge R, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia 2002;43:1161-7.
111. Pennell P, Newport D, Stowe Z, et al. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004;62:292-5.
112. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: Pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000;41:709-13.
113. Tran T, Leppik I, Blesi K, et al. Lamotrigine clearance during pregnancy. Neurology 2002;59:251-5.
114. Mackay F, O'Brien T, Hitchcock A. Safety of long term lamotrigine in epilepsy. Epilepsia 1997;38:881-6.
115. Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and lactation. Ann Pharmacother 2004;38: 1265-71.
116. McKenna K, Koren G, Tetelbaum M, et al. Pregnancy outcome of women using atypical antipsychotic drugs: A prospective comparative study. J Clin Psychiatry. 2005;66:444-9.
117. Barnas C, Bergant A, Hummer A, et al. Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 1994;151:945.
118. Di Michele V, Ramenghi L, Sabatino G. Clozapine and lorazepam administration in pregnancy. Eur Psychiatry 1996;11:214.
119. Kornhuber J, Weller M. Postpartum psychosis and mastitis: A new indication for clozapine? Am J Psychiatry 1991;148:1751-2.
120. Dev V, Krupp P. The side-effects and safety of clozapine. Rev Contemporary Pharmacotherapy 1995;6:197-208.
121. Dickson R, Hogg L. Pregnancy of a patient treated with clozapine. Psychiatr Serv 1998;49:1081-3.
122. Iqbal M, Rahman A, Husain Z, et al. Clozapine: A clinical review of adverse effects and management. Ann Clin Psychiatry 2003;15:33-48.
123. Goldstein D, Corbin L, Fung M. Olanzapine-exposed pregnancies and lactation: Early experience. J Clin Psychiatry 2000;20:399-403.
124. Ernst C, Goldberg J. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry 2002;63(suppl 4):42-55.
125. Patton S, Misri S, Corral M, et al. Antipsychotic medication during pregnancy and lactation in women with schizophrenia: Evaluating the risk. Can J Psychiatry 2002;47:959-65.
126. Croe S, Buist A, Hackett L, et al. Olanzapine excretion in human breast milk: Estimation of infant exposure. Int J Neuropsychopharmacol 2002;5:243-7.
127. Gardiner S, Kristensen J, Begg E, et al. Transfer of olanzapine into breast milk, calculation of infant drug dose, and effects on breast-fed infants. Am J Psychiatry 2003;160:1428-31.
128. Ratnayake T, Libretto S. No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry 2002;63:76-7.
129. Physician's desk reference 2002 psychotropic prescribing guide, 5th Edition. Montvale, NJ: Thomson Medical Economics; 2002:299.
130. Aichhorn W, Stuppaeck C, Whitworth AB. Risperidone and breast-feeding. J Psychopharmacol 2005;19:211-3.
131. Tenyi T, Trixler M, Keresztes Z. Quetiapine and pregnancy (letter). Am J Psychiatry 2002;159:674.
132. Lee A, Giesbrecht E, Dunn E, et al. Excretion of quetiapine in breast milk. Am J Psychiatry 2004;161:1715-6.
133. Product information. Abilify (aripiprazole). Princeton, NJ: Bristol-Myers Squibb, Aug 2003.
134. Trixler M, Tenyi T. Antipsychotic use in pregnancy. What are the best treatment options? Drug Saf 1997;16:403-10.
135. James M. Neuroleptic malignant syndrome in pregnancy. Psychosomatics 1988;29:112-9.
136. Cleary M. Fluphenazine decanoate during pregnancy. Am J Psychiatry 1977;134:815-6.
137. Hill R, Desmond M, Kay J. Extrapyramidal dysfunction in an infant of a schizophrenic mother. J Pediatr 1966;69:589-95.
138. Slone D, Siskind V, Heinonen O, et al. Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score. Am J Obstet Gynecol 1977;128:468-86.
139. Roberton R, Majka J, Peter C, et al. Effects of prenatal exposure to chlorpromazine on postnatal development and behavior of rats. Toxicol Appl Pharmacol 1980;53:541-9.
140. Roberton R, Majka J, Peter C, et al. Effects of prenatal exposure to chlorpromazine on postnatal development and behavior of rats. Toxicol Appl Pharmacol 1980;53:541-9.
141. Aarkog D. Association between maternal intake of diazepam and oral clefts (letter). Lancet 1975;2:921.
142. Saxen I, Saxen L. Association between maternal intake of diazepam and oral clefts (letter). Lancet 1974;2:498.
143. Entman S, Vaughn W. Lack of relation of oral clefts to diazepam use in pregnancy. N Engl J Med 1984;310:1121-2.
144. Rosenberg L, Mitchell A, Parsells J, et al. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1984;309:1281-5.
145. Shiono P, Mills J. Oral clefts and diazepam use during pregnancy. N Engl J Med 1984;311:919-20.
146. Barry W, St Clair S. Exposure to benzodiazepines in utero. Lancet 1987;1:1436-7.
147. Schick-Boschetto B, Zuber C. Alprazolam exposure during early human pregnancy. Teratology 1992;45:460.
148. Dolovich L, Addis A, Vaillancourt J, et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: Meta-analysis of cohort and case-control studies. BMJ 1998;317: 839-43.
149. Erkkola R, Kero P, Kanto J, et al. Severe abuse of psychotropic drugs during pregnancy with good perinatal outcome. Ann Clin Res 1983;15:88-91.
150. Fisher J, Edgren B, Mammel M, et al. Neonatal apnea associated with clonazepam therapy: A case report. Obstet Gynecol 1985;66:348-58.
151. Haram K. Floppy infant syndrome and maternal diazepam. Lancet 1977;2:612-3.
152. Kriel R, Cloyd J. Clonazepam and pregnancy (letter). Ann Neurol 1982;11:544.
153. Athinarayanan P, Peirog S, Nigam S, et al. Chlordiazepoxide withdrawal in the neonate. Am J Obstet Gynecol 1976;124:212-3.
154. Bitnum S. Possible effects of chlordiazepoxide on the foetus Canadian Medical Association Journal 1969;100;351.
155. Stirrat G, Edington P, Berry D. Transplacental passage of chlordiazepoxide. BMJ 1974;2:729.
156. Backes C, Codero L. withdrawal symptoms in the neonate from presumptive intrauterine exposure to diazepam: Report of case. J Am Osteopath Assoc 1980;79:584-5.
157. Miller L. Clinical strategies for the use of psychotropic drugs during pregnancy. Psychiatr Med 1991;9:275-98.
158. Iqbal M, Aneja A, Fremont W. Effects of chlordiazepoxide (Librium) during pregnancy and lactation. Conn Med 2003;67:259-62.
159. Erkkola R, Kanto J, Sellman R. Diazepam in early human pregnancy. Acta Obstet Gynecol Scand 1974;135-8.
160. Mandelli M, Morselli P, Nordio S, et al. Placental transfer of diazepam and its disposition in the newborn. Clin Pharmacol Ther 1975;17:564-72.
161. Whitelaw A, Cummings A, McFadyen I. Effect of maternal lorazepam on the neonate. BMJ 1981;282:1106-8.
162. Laegreid L, Olegard R, Wahlstrom J, et al. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1997;2:108-9.
163. Hartz S, Heinonen O, Shapiro S, et al. Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. N Engl J Med 1975;292:726-8.
164. Gavish M, Avnimelech-Gigus N, Feldon J, et al. Prenatal chlordiazepoxide effects on metrazol seizures and benzodiazepine receptor density in adult albino rats. Life Sci 1984;36:1693-8.
165. Wreitland M. Excretion of oxazepam in breast milk. Eur J Clin Pharmacol 1987;33:209-10.
antidepressants; antipsychotics; benzodiazepines; mood stabilizers; pregnancy; lactation; breast-feeding; teratogenic effects
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