Evidence-Based Reviews

Treating bipolar disorder during pregnancy

Current Psychiatry. 2003 July;2(7):14-26

References

1. Altshuler L, Cohen L, Szuba, et al. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 1996;153:592-606.

2. Nelson K, Holmes LB. Malformations due to presumed spontaneous mutations in newborn infants. N Engl J Med 1989;320:19-23.

3. Viguera AC, Nonacs R, Cohen LS, et al. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry 2000;157:179-84.

4. Steer RA, Scholl TO, Hediger ML, Fischer RL. Self-reported depression and negative pregnancy outcomes. J Clin Epidemiol 1992;45(10):1093-9.

5. Orr ST, Miller CA. Maternal depressive symptoms and the risk of poor pregnancy outcome. Review of the literature and preliminary findings. Epidemiol Rev 1995;17(1):165-71.

6. Zuckerman B, Amaro H, Bauchner H, Cabral H. Depressive symptoms during pregnancy: relationship to poor health behaviors. Am J Obstet Gynecol 1989;160:1107-11.

7. Miller LJ. Psychotic denial of pregnancy: phenomenology and clinical management. Hosp Community Psychiatry 1990;41:1233-7.

8. Cohen LS, Friedman JM, Jefferson JW, et al. A reevaluation of risk of in utero exposure to lithium. JAMA 1994;271(2):146-50correction JAMA 1994;271(19):1485.

9. Schou M. What happened later to the lithium babies? A follow-up study of children born without malformations. Acta Psychiatr Scand 1976;54(3):193-7.

10. Woody JN, London WL, Wilbanks GD. Lithium toxicity in a newborn. Pediatrics 1971;47:94-6.

11. Jones K, Lacro R, Johnson K, Adams J. Patterns of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989;320:1661-6.

12. Rosa F. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991;324(10):674-7.

13. Koch S, Losche G, Jager-Roman E, et al. Major and minor birth malformations and antiepileptic drugs. Neurology 1992;42:83-8.

14. 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.

15. Nakane Y, Okuma T, Takahashi R, et al. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epilepsia 1980;21:663-80.

16. Edlund MJ, Craig TJ. Antipsychotic drug use and birth defects: an epidemiologic reassessment. Compr Psychiatry 1984;25:32-8.

17. Kris EB. Children of mothers maintained on pharmacotherapy during pregnancy and postpartum. Curr Ther Res 1965;7:785-9.

18. Clark CVH, Gorman D, Vernadakis A. Effects of prenatal administration of psychotropic drugs on behavior of developing rats. Dev Psychobiol 1970;3:225-35.

19. Golub M, Kornetsky C. Seizure susceptibility and avoidance conditioning in adult rats treated prenatally with chlorpromazine. Dev Psychobiol 1974;7:79-88.

20. Spear LP, Shalaby IA, Brick J. Chronic administration of haloperidol during development: behavioral and psychopharmacological effects. Psychopharmacology (Berl) 1980;70:47-58.

21. Cagiano R, Barfield RJ, White NR, et al. Subtle behavioral changes produced in rat pups exposed in utero to haloperidol. Eur J Pharmacol 1988;157:45-50.

22. Rieder RO, Rosenthal D, Wender P, Blumenthal H. The offspring of schizophrenics: fetal and neonatal deaths. Arch Gen Psychiatry 1975;32:200-11.

23. Sobel DE. Fetal damage due to ECT, insulin coma, chlorpromazine, or reserpine. Arch Gen Psychiatry 1960;2:606-11.

24. Dickson R. Olanzapine and pregnancy. Can J Psychiatry 1998;43:196-7.

25. Goldstein DJ, Corbin LA, Fung MC. Olanzapine-exposed pregnancies and lactation; early experience. J Clin Psychopharmacol 2000;24(4):399-403.

26. Altshuler LL, Cohen LS, Moline ML, et al. The expert consensus guideline series: treatment of depression in women. Postgrad Med 2001 Mar;(Spec No):1-22.

27. Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010-15.

28. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in the neonate. Pediatrics 1993;92:721-2.

29. Cabrera FM, Battaglia G. Delayed decreases in brain 5-HT 2a and 2c receptor density and function in male rat progeny following prenatal fluoxetine. J Pharmacol Exp Ther 1994;269:637-45.

30. Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry 1994;45:444-50.

31. Ferrill MJ, Kehoe WA, Jacisin JJ. ECT during pregnancy: physiologic and pharmacologic considerations. Convuls Ther 1992;8:186-200.

32. Yonkers K, Wisner K, Cohen L, et al. Management of bipolar disorder during pregnancy and the postpartum period. Bipolar Consensus Statement. Submitted for publication.

33. Dansky L, Rosenblatt D, Andermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurology 1992;42(suppl 5):32-42.

34. Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology 1992;42(suppl 5):17-24.

35. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-7.

36. Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003;160:555-62.

37. Lam DH, Watkins ER, Hayward P, et al. A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome in the first year. Arch Gen Psychiatry 2003;60(2):145-52.

Neural tube defects. Data associate anticonvulsant exposure with a significantly greater risk for malformations than in the general population. Specifically, anticonvulsants may cause neural tube defects such as spina bifida, ancephaly, and encephaly in 2 to 5% of those exposed, as well as craniofacial anomalies, microcephaly, growth retardation, and heart defects.^11-14

Table 2

FDA’s teratogenicity ratings of mood stabilizers and other antimanic agents

Category	Medication	Teratogenicity
Mood stabilizers	Lithium Carbamazepine Valproate	Category D Category D Category D
Anticonvulsants	Gabapentin Lamotrigine Topiramate	Category C Category C Category C
Antipsychotics	Olanzapine Risperidone Chlorpromazine Haloperidol Trifluoperazine	Category C Category C Safety in pregnancy not known Category C Safety in pregnancy not known
Source: Physicians’ Desk Reference. Montvale, NJ: Medical Economics Co., 2003.

More minor malformations—such as rotated ears, depressed nasal bridge, short nose, elongated upper lip, and fingernail hypoplasia—have been reported in infants exposed to anticonvulsants in utero.¹⁴ These malformations disappear with age.¹³ Teratogenicity increases with the use of multiple anticonvulsants and possibly with higher maternal plasma levels and toxic metabolites.¹⁵

Conclusion. The three most commonly used mood stabilizers are all teratogenic. The least risk may occur with lithium (0.1%) versus valproate (2 to 5%) or carbamazepine (1 to 3%). These risks must be weighed against the up to 50% chance of relapse with medication discontinuation.³

ANTIPSYCHOTICS

Antipsychotics are often used to treat mania because of their rapid effects and sedative properties. Most antipsychotics—specifically, haloperidol, olanzapine, and risperidone—are labeled “C,” specifying that fetal risk cannot be ruled out.

Table 3

FDA’s teratogenicity ratings of common antidepressants

Category	Medication	Teratogenicity
Tricyclics	Amitriptyline Clomipramine Desipramine Imipramine Nortriptyline	Category C Category C Safety in pregnancy not known Safety in pregnancy not known Safety in pregnancy not known
Selective serotonin reuptake inhibitors	Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline	Category C Category C Category C Category C Category C
Other antidepressants	Bupropion Phenelzine Tranylcypromine	Category B Safety in pregnancy and nursing not known Safety in pregnancy and nursing not known
Source: Physicians’ Desk Reference. Montvale, NJ: Medical Economics Co., 2003.

Chlorpromazine and haloperidol have been most studied during pregnancy but in relation to treating hyperemesis gravidarum and psychosis, not bipolar disorder. Results regarding antipsychotics’ teratogenic and behavioral risks are mixed,^16-21 probably because the various compounds have different effects on the fetus.

The underlying illness—rather than the medications—may increase the rate of anomalies seen with exposure to antipsychotics:

Rieder et al²² reported an increased rate of perinatal death in infants of schizophrenic mothers but no significant association between the mothers’ use of antipsychotics and perinatal death.
Sobel²³ compared psychotic women with and without histories of chlorpromazine exposure during pregnancy. Rates of fetal damage were similar and approximately twice that of the general population.

A meta-analysis of 74,337 live births revealed that first-trimester exposure to low-potency antipsychotics increases the relative risk of fetal anomalies in nonpsychotic women. Phenothiazines may increase the 2% baseline incidence of malformations to 2.4%.¹ No specific organ malformation following fetal exposure to phenothiazines has been consistently identified.

Olanzapine was recently approved for treating mania. Very little data exist regarding its impact on fetal development when used during pregnancy, although studies on small numbers of women have not revealed teratogenicity.^24,25

Conclusion. Psychotic illness itself may increase the risk of poor fetal outcome to a greater extent than does antipsychotic use. Prenatal exposure to low-potency phenothiazines may further increase this risk, although only slightly. The effect of prenatal exposure to atypical antipsychotics requires further study.

BENZODIAZEPINES

Benzodiazepines are rarely a primary treatment for mania or depression. Thus, a comprehensive review of their effect on fetal outcome is beyond the scope of this review. A meta-analysis of exposure in the first trimester suggests a very small but significant increase in risk for cleft palate.¹ The absolute risk is <1 in 1,000 cases.

ANTIDEPRESSANTS

Whereas treatment of acute mania is considered a medical emergency, women with bipolar disorder may also relapse into depression during pregnancy. An antidepressant should not be used without a mood stabilizer when treating bipolar I disorder, although a mood stabilizer alone may be inadequate to treat depression. Using tricyclics and selective serotonin reuptake inhibitors (SSRIs) during pregnancy has not been associated with teratogenicity (Table 3),²⁶ although perinatal effects have been reported.¹

Tricyclics. In case-control studies involving more than 300,000 live births, 414 incidences of first-trimester exposure to tricyclics were followed. Information from these patients found no significant association between fetal exposure to tricyclics and increased rates of congenital malformations.¹ The few studies that have been performed suggest no long-term effects from in utero exposure.²⁶ Although these results suggest that prenatal exposure to tricyclics is relatively safe, more research is needed.

SSRIs. To date, no significant teratogenic effects of SSRIs have been identified in offspring of treated women.

The manufacturer’s register for fluoxetine contains approximately 2,000 cases of treated patients, with no excess cases of congenital anomalies or malformations following prenatal exposure. Citalopram has the next largest database of in utero exposure (n=365), again with no increased risk for teratogenicity. Several smaller systematic reports are available on in utero exposure to sertraline, paroxetine, or escitalopram.²⁶