Lithium is the first-line treatment for pregnant patients requiring medication (SOR: C, based on expert opinion). Monotherapy is preferred for women of childbearing age who have bipolar disorder (strength of recommendation [SOR]: C, based on expert opinion)

Atlas, Michel C.

Minick, Genevieve

University of Missouri: MOspace

	 vol	56,	No	8	/	August	2007	 665www.jfponline.comCliniCal INquIrIes From the Family Physicians Inquiries Networkfast trackz Evidence summaryData on the treatment of bipolar dis-ease among fertile women are limited to case-control studies and drug registries because of a lack of RCTs in this popu-lation.1 Onset of bipolar illness often occurs in the teens and twenties, which puts women with bipolar disorder at risk for having episodes requiring treat-ment during their childbearing years. Treatment might be initiated for a non-pregnant patient, but you must consider potential pregnancy when choosing a medication.The TablE shows common medica-tions used in bipolar illness, their risk cat-egories for pregnancy and lactation, and monitoring recommendations.1–5  What’s the best strategy  for bipolar disorder  during pregnancy?lithium	is	the	first-line	treatment	for	pregnant	patients	requiring	medication	(sor:	C,	based	on	expert	opinion).		 Monotherapy	is	preferred	for	women	of	childbearing	age	who	have	bipolar	disorder	(strength	of	recommendation	[sor]:	C,	based	on	expert	opinion).		 When	prescribing	lithium	or	anticonvulsant	drugs	(eg,	valproic	acid	and	carbamazepine),	draw	blood	levels	monthly	during	the	first	and	second	trimesters,	and	then	weekly	in	the	third	trimester	(sor:	C,	based	on	expert	opinion).		 give	all	pregnant	women	taking	medications	for	the	prevention	of	mania	a	detailed	fetal	anatomy	ultrasound	at	18	to	20	weeks	(sor:	C,	based	on	expert	opinion).		 Behavior	therapy	has	a	role	as	an	adjunct	to	pharmacologic	therapy,	but	no	studies	show	its	benefit	alone	in	preventing	mania	(sor:	C,	based	on	expert	opinion).		 electroconvulsive	therapy	may	be	beneficial	for	patients	with	refractory	depressive	symptoms,	and	may	be	used	in	pregnancy	(sor:	C,	based	on	expert	opinion).	Psychiatric consultation is essentialunfortunately,	the	medications	used	to	treat	this	serious	health	problem	can	also	have	important	negative	effects	on	a	patient’s	health.	Although	the	principles	outlined	here	are	helpful	guidelines,	in	practice	I	rarely	treat	patients	with	bipolar	disorder	without	psychiatric	consultation.		 As	family	physicians,	it’s	critical	that	we	address	reliable	contraception	and	the	importance	of	preconception	planning	with	women	early	in	the	course	of	this	psychiatric	illness.Heather Paladine, MDuniversity	of	southern	California,	san	gabrielClinical commentaryEvidence-based answerGenevieve Minick, MDGuthrie Family Medicine  Residency, Sayre, PaMichel atlas, MlSKornhauser Health Sciences Library, University of Louisville, Louisville, KyMonotherapy  is preferred;  it generally  minimizes risk  of congenital anomaliesCoNt INueD666 vol	56,	No	8	/	August	2007		ThE Journal of family PraCTiCEtable  PrEgnanCy laCTaTion    safETy  safETy TrEaTmEnT CaTEgory* CaTEgory† Dosing anD moniToringlithium	 D	 l4	 More	frequent	dosing	maintains	therapeutic	levels	and	avoids	peaks;			 	 	 	 it’s	unclear	if	this	benefits	the	fetus			 	 	 	 Detailed	ultrasound	in	second	trimester		 	 	 	 Monthly	levels	during	1st	and	2nd,	weekly	during	3rd	trimester		 	 	 	 Decrease	dose	during	delivery,	up	to	50%	anTiConvulsanTsCarbamazepine (Tegretol)	 C/D	 l2	 Contraindicated	in	1st	trimester		 	 	 	 Monthly	levels	during	2nd	trimester,	weekly	during	3rd	trimester	lamotrigine (lamictal)	 C	 l3		 Keep	daily	dose	under	200	mg	to	reduce	risk	of	congenital	anomaliesoxcarbazepine (Trileptal)	 C	 l3		 Decreases	level	of	oral	contraceptivesTopiramate (Topamax)	 C	 l3		 Decreases	level	of	oral	contraceptivesvalproic acid (Depakene)	 D	 l2	 once-daily	dosing	may	cause	unpredictably	high	peak	levels		 	 	 	 Contraindicated	in	1st	trimester			 	 	 	 Monthly	levels	during	2nd	trimester,	weekly	during	3rd	trimester	anTiPsyChoTiCs (TyPiCal anD aTyPiCal)haloperidol (haldol)	 C	 l2		 First-generation	agents	recommended	in	1st	trimester	to	decrease		Chlorpromazine (Thorazine)	 C	 l3	 risk	of	malformations	and	for	recurrence	of	symptoms	during			 	 	 	 pregnancy	among	unmedicated	patientsaripiprazole (abilify)	 C	 l3		Clozapine (Clozaril)	 C/B	 l3		olanzapine (Zyprexa)	 C	 l3		Quetiapine (seroquel)	 C	 l4		risperidone (risperdal)	 C	 l3		Ziprasidone (geodon)	 C	 l4		 Does	not	decrease	effectiveness	of	oral	contraceptivesBEnZoDiaZEPinEsalprazolam	 D	 l3		 	 	 	Diazepam	 D	 l3/l4	for	 useful	for	regulating	sleep;	may	prevent	postpartum	relapse			 	 	 chronic	use	 of	manialorazepam 	 D		 l3		 High	potency	preferred	due	to	shorter	half-lifeClonazepam	 C/D	 l3	CarDiovasCular or anTihyPErTEnsivE agEnTsverapamil	 C	 l2		 efficacy	unproven	in	mania	of	bipolar	disorder		 	 	 	 Monitor	blood	pressure,	especially	if	normotensive*Pregnancy risk categories:    † lactation risk categories from hale:4a		safety	demonstrated	in	human	studies.	 	 	 l1		safestB		safety	presumed	based	on	animal	studies.	 	 	 l2		saferC			uncertain	safety	with	no	human	or	animal	studies		 	 l3		Moderately	safeshowing	adverse	effects.	 	 	 l4		Possibly	hazardousD			unsafe;	evidence	of	risk	that	may	be	acceptable		 	 l5		Contraindicated	in	certain	situations.X		Highly	unsafe	and/or	a	teratogen.Management of bipolar disorder during pregnancy: Drugs, safety categories for pregnancy and lactation, and monitoring recommendationsfast trackwww.jfponline.com 	 vol	56,	No	8	/	August	2007	 667Treat beyond  delivery—and monitor the infant closelylithium is first-line treatment Monotherapy for bipolar illness is pre-ferred; it generally minimizes the risk of congenital anomalies. The use of lithium for long-term management of bipolar disorder is associated with de-creased rates of suicide and all-cause mortality.6is risk of Ebstein’s anomaly a factor? Lithium is associated with 10- to 20-fold higher risk of Ebstein’s anomaly, a con-genital anomaly affecting the tricuspid valve and right ventricle, with varying clinical effects. However, the absolute risk is small: Ebstein’s anomaly occurs in 1:20,000 unexposed pregnancies.2,7,8 Because concerns about this anomaly are less of a problem than once thought, lithium is the first-line treatment for bi-polar disorder in pregnancy.7 Discontinue with care. The risk of recurrence of mania is 3 times higher with rapid discontinuation of lithium over less than 2 weeks.2,7 Taper lithium over 2 to 4 weeks when discon-tinuing the medication.7 Women taking lithium may already be pregnant when you see them, and even a slow lithium taper may not minimize ex-posure to the developing fetus.2,8 Thoroughly discuss the risks and benefits of continued treatment and close monitoring compared with discontinua-tion. anticonvulsants and antipsychotics pose their share of risksantiseizure medications, including car-bamazepine and valproic acid, are con-sidered human teratogens in the first tri-mester.9 If a woman has an unplanned pregnancy and presents late in the first trimester or in the second trimester, discontinuation of these medication in stable patients is not recommended. Valproate and carbamazepine are both compatible with breastfeeding. Although lamotrigine was thought to have fewer risks than other drugs, the FDA issued an alert in September 2006 suggesting a possible increased risk of cleft palate for infants exposed to la-motrigine in the first trimester.10 Typical antipsychotics appear to be safe in pregnancy, but they can have side effects for the mother. These side effects include extrapyramidal symptoms, such as tardive dyskinesia and hyperprolactinemia. atypical antipsychotics have not been well studied, but there is no conclusive evidence that they cause fetal malforma-tions.1100-fold higher risk  of postpartum psychosisWomen with bipolar disorder have a 100-fold higher risk of developing post-partum psychosis.2 For this reason, treatment beyond de-livery is recommended, along with close monitoring of the infant.  Drug monitoring and dosingsecond and third trimesters. Monitor the levels of lithium and anticonvulsants monthly through the second trimester, then weekly during the third trimester because of blood volume changes.2 Medication doses may also need to be increased up to 50% during the sec-ond and third trimesters, when creatinine clearance doubles and the plasma volume increases.8 Postpartum. Following delivery, you’ll need to decrease the dose of lithium to prepregnancy doses, unless there is an acute destabilization of mood.2 Verapamil for bipolar disorder? Wisner et al11 found verapamil to be ef-fective for mania in a nonrandomized prospective study of bipolar hypomanic/manic and depressed patients. Verapamil has been used for patients with hypertension during pregnancy, and studies that have looked at outcomes of pregnancies with exposure to verapamil showed no adverse drug related effects. Cognitive therapy may helpCognitive behavior therapy—which focuses on adherence to treatment, bipolar disorder and pregnancyfast track668 vol	56,	No	8	/	August	2007		ThE Journal of family PraCTiCECliniCal INquIrIesminimizing stressors, improving social and occupational function, and minimiz-ing sleep deprivation—may help prevent mania, although there have been no studies specifically on prevention of ma-nia using cognitive behavior therapy.1,2 Is ECT teratogenic?There have been no conclusive reports of teratogenicity with electroconvulsive therapy.2 The most common complication, occurring in 1.5% of cases, were fetal arrhythmias.  Avoiding atropine, main-taining oxygenation, avoiding exces-sive hyperventilation, and elevating the right hip can decrease the risk of fetal arrhythmias during electroconvulsive therapy.5 Recommendations from others Educate the mother and family on the impact of mental health and illness on a pregnant woman and the fetus, and the risks of medications during breast-feeding. aPa Practice guideline. According to the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Bipolar Disorder:6  • Women with bipolar disorder should plan their pregnancies. • Physicians should encourage pa-tients to use contraception and seek pre-conception counseling.  • Because of genetic risks associated with bipolar disorder, patients may also benefit from genetic counseling. • High-potency antipsychotics are preferred during pregnancy because they are less likely to have associated anticho-linergic, antihistaminergic, or hypoten-sive effects.Best Practices and Research in Clinical Obstetrics and Gynaecology from the UK suggests:12 •  delaying conception until illness is in remission, •  discussing contraception,  •  coordinating with psychiatric con-sultants before pregnancy, and •  reviewing teratogenic effects of medications with the patient.   nreferences 	 1.	 	eberhard-gran	M,	eskild	A,	opjordsmoen	s.	treat-ing	mood	disorders	during	pregnancy:	safety	con-siderations.	Drug Safety	2005;	28:695–706.	 2.	 	Burt	vK,	rasgon	N.	special	considerations	in	treat-ing	bipolar	disorder	in	women.	Bipolar Disord	2004;	6:2–13.	 3.	 	Briggs	gg,	Freeman	rK,	Yaffe	sJ.	Drugs in Preg-nancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 6th	ed.	Philadelphia:	lippincott,	Williams	and	Wilkins;	2002.	 4.	 	Hale	tW.	Medications and Mother’s Milk.	12th	ed.	Amarillo,	tex:	Hale	Publishing;	2006.	 5.	 	Iqbal	MM,	sohhan	t,	Mahmud	sZ.	the	effects	of	lithium,	 valproic	 acid,	 and	 carbamazepine	 during	pregnancy	 and	 lactation.	 J Toxicol Clin Toxicol 2001;	39:381–392.	 6.	 	American	Psychiatric	Association.	Practice	guide-line	 for	 the	 treatment	of	patients	with	bipolar	dis-order	(revision).	Am J Psychiatry	2002;	159(4	sup-pl):1–50.		 7.	 	Freeman	 MP,	 gelenberg	 AJ.	 Bipolar	 disorder	 in	women:	reproductive	events	and	treatment	consid-erations.	Acta Psychiatr Scand 2005;	112:88–96.	 8.	 	Yonkers	KA,	Wisner	Kl,	stowe	Z,	et	al.	Manage-ment	 of	 bipolar	 disorder	 during	 pregnancy	 and	the	 postpartum	 period.	 Am J Psychiatry	 2004;	161:608–620.	 9.	 	gentile	 s.	 Prophylactic	 treatment	 of	 bipolar	 dis-order	 in	 pregnancy	 and	 breastfeeding:	 focus	 on	emerging	 mood	 stabilizers.	 Bipolar Disord	 2006;	8:207–220.	10.	 	Information	for	Healthcare	Professionals	lamotrig-ine	(marketed	as	lamictal).	FDA	Advisory,	septem-ber	28,	2006.	Available	at:	www.fda.gov/cder/drug/Infosheets/HCP/lamotrigineHCP.htm.	 Accessed	on	June	26,	2007.	11.	 	Wisner	Kl,	Peindl	Ks,	Perel	JM,	Hanusa	BH,	Piontek	CM,	Baab	s.	verapamil	 treatment	 for	women	with	bipolar	disorder.	Biol Psychiatry	2002;	51:745–752.12.	 	Craig	M,	Abel	K.	Drugs	 in	pregnancy.	Prescribing	for	 psychiatric	 disorders	 in	 pregnancy	 and	 lacta-tion.	Best Pract Res Clin Obstet Gynaecol	 2001;	15:1013–1030.APA: High-potency  antipsychotics are preferable during pregnancy; they're less likely to cause anticholinergic, antihistaminergic, or hypotensive  effects

What's the best strategy for bipolar disorder during pregnancy?

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