Clinical Review

What Ob/Gyns need to know about drug therapy in bipolar gravidas

OBG Manag. 2004 January;16(1):27-38

References

1. Altshuler L, Cohen L, Szuba MP, 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;157:179-184.

4. Steer RA, Scholl TO, Hediger ML, Fischer RL. Self-reported depression and negative pregnancy outcomes. J Clin Epidemiol. 1992;45:1093-1099.

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;17:165-171.

6. Zuckerman B, Amaro H, Bauchner H, Cabral H. Depressive symptoms during pregnancy: relationship to poor health behaviors. Am J Obstet Gynecol. 1989;160:1107-1111.

7. Miller LJ. Psychotic denial of pregnancy: phenomenology and clinical management. Hosp Community Psychiatry. 1990;41:1233-1237.

8. Cohen LS, Friedman JM, Jefferson JW, et al. A reevaluation of risk of in utero exposure to lithium. JAMA. 1994;271:146-150;correction JAMA. 1994;271:1485.

9. Schou M. What happened later to the lithium babies? A follow-up study of children born without malformations. Acta Psychiatr Scand. 1976;54:193-197.

10. Woody JN, London WL, Wilbanks GD. Lithium toxicity in a newborn. Pediatrics. 1971;47:94-96.

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;320:1661-1666.

12. Rosa F. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med. 1991;324:674-677.

13. Koch S, Losche G, Jager-Roman E, et al. Major and minor birth malformations and antiepileptic drugs. Neurology. 1992;42:83-88.

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;21:663-680.

16. Edlund MJ, Craig TJ. Antipsychotic drug use and birth defects: an epidemiologic reassessment. Compr Psychiatry. 1984;25:32-38.

17. Kris EB. Children of mothers maintained on pharmacotherapy during pregnancy and postpartum. Curr Ther Res. 1965;7:785-789.

18. Clark CVH, Gorman D, Vernadakis A. Effects of prenatal administration of psychotropic drugs on behavior of developing rats. Dev Psychobiol. 1970;3:225-235.

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;32:200-211.

23. Sobel DE. Fetal damage due to ECT, insulin coma, chlorpromazine, or reserpine. Arch Gen Psychiatry. 1960;2:606-611.

24. Dickson R. Olanzapine and pregnancy. Can J Psychiatry. 1998;43:196-197.

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

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;335:1010-1015.

28. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in the neonate. Pediatrics. 1993;92:721-722.

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;269:637-645.

30. Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry. 1994;45:444-450.

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;338:131-137.

36. Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry. 2003;160:555-562.

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;60:145-152.

38. US Food and Drug Administration. Current categories for drug use in pregnancy. Available at: http://www.fda.gov/fdac/features/2001/301_preg.html#categories. Accessed November 19, 2003.

Mood stabilizers

The 3 most commonly used mood stabilizers—lithium, valproate, and carbamazepine—are 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

The FDA designates these 3 medications as category as “D” agents (TABLE 2). This rating implies that studies have demonstrated fetal risk; still, the drug’s potential benefit may outweigh the risk.

Lithium. The International Registry of Lithium reported increased rates of cardiovascular malformations—such as Ebstein’s anomaly—in children whose mothers took lithium during pregnancy.

• Relative risk for Ebstein’s anomaly in children with fetal exposure to lithium may be 20 times higher than the risk in unexposed children, although the absolute risk with lithium exposure remains low (1 in 1,000 births).^1,8

No significant neurobehavioral teratogenicity has been reported in infants exposed in utero to lithium, although few cases have been studied. One study reported that 22 lithium-exposed infants attained developmental milestones at a pace comparable to that of unexposed controls.⁹

•“Floppy baby” syndrome, in which infants experience hypotonicity and cyanosis, is the most recognized adverse effect in infants exposed to lithium in utero.¹⁰ Its frequency is unknown, but rare. Neonatal hypothyroidism and nephrogenic diabetes insipidus have also been documented.

Anticonvulsants. To date, no studies have examined the outcomes of children whose mothers took anticonvulsants for bipolar disorder during pregnancy, though the research concerning epileptic mothers is extensive.

• Neural tube defects. Infants exposed to anticonvulsant agents have a significantly greater risk for malformations than do neonates 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

• Other 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

TABLE 2

FDA teratogenicity ratings of mood stabilizers, antimanic drugs, and antidepressants

MEDICATION	PREGNANCY CATEGORY
Mood stabilizers
Lithium	D
Carbamazepine	D
Valproate	D
Anticonvulsants
Gabapentin	C
Lamotrigine	C
Topiramate	C
Antipsychotics
Olanzapine	C
Risperidone	C
Chlorpromazine	C
Haloperidol	C
Trifluoperazine	C
Tricyclic antidepressants
Amitriptyline	C
Clomipramine	C
Desipramine	C
Imipramine	C
Nortriptyline	D
Selective serotonin reuptake inhibitors
Citalopram	C
Escitalopram	C
Fluoxetine	C
Fluvoxamine	C
Paroxetine	C
Sertraline	C
Other antidepressants
Bupropion	B
Phenelzine	C
Tranylcypromine	C

Antipsychotics

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 additional study.

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

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 mother’s 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 lowpotency 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, though studies on small numbers of women have not revealed teratogenicity.^24,25

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 during the first trimester suggests a very small but significant increase in risk for cleft palate.¹ The absolute risk with exposure appears to be less than 1 in 1,000 cases.

Antidepressants

Acute mania is an emergency requiring immediate treatment. The other possibility in women with bipolar disorder is relapse into depression. An antidepressant should not be used without a mood stabilizer when treating bipolar I disorder. Similarly, a mood stabilizer alone may be inadequate to treat depression. The use of tricyclics or selective serotonin reuptake inhibitors (SSRIs) during pregnancy has not to date been associated with teratogenicity (TABLE 3),²⁶ but larger numbers of women need to be studied. Perinatal effects in some cases have been reported.¹