Lithium in pregnancy & lactation—safer than we thought?

There are few topics more controversial than medication use in pregnancy and lactation. Well-intentioned friends, family and even healthcare professionals may often advise a woman to stop any and all medications while she is pregnant. Unfortunately they neglect to note the adverse effects of untreated illness in pregnancy and lactation on both mother and child, not to mention the increasing evidence-base available about the true benefits and risks of medications such as lithium in pregnancy.

Bipolar illness can be particularly difficult to manage in pregnancy, and women are often advised to not have children. Previous thinking that pregnancy was protective against mood disorder symptoms has been disproven. One study found similar rates of symptom recurrence during pregnancy whether or not lithium was continued, but a much higher rate of post-partum symptoms of mania, depression or mixed dysphoria when lithium was discontinued.¹ A more recent study found that the overall risk of at least one recurrence in pregnancy with or without medications was 71%, with a twofold greater overall risk when a mood stabilizer was discontinued (85.5% vs 37%).² The median time to recurrence was fourfold shorter, and the proportion of time spent ill was five times greater in the group that discontinued pharmacotherapy.² Untreated illness not only increases the risk of accidents, substance abuse, medical disorders and suicide for mother,² but it also increases the risk of antepartum hemorrhage, prematurity, low birth weight, and intrauterine growth retardation in the fetus.³

As noted in the above studies, there is still a risk of recurrence of symptoms even when a woman remains on lithium. This may be in part because maternal lithium levels are subject to fluctuations that may not be monitored closely enough, leading to a lack of appropriate dosage adjustment. Pregnancy symptoms such as vomiting may lead to dehydration and a rapid increase in lithium levels.³ Late pregnancy is a time of particular concern, as changes in glomerular filtration rate can alter lithium clearance, and increased frequency of urination may reduce lithium levels.⁴ Because the glomerular filtration rate returns to normal postpartum, a decrease in dose at that time is also recommended.⁴

But what are the known risks of lithium in pregnancy? The most commonly associated complication with lithium is Ebstein's anomaly, a congenital cardiovascular defect. This was based mostly on a 1983 report from the International Registry of Lithium-Exposed Babies that retrospectively found 225 cases of Ebstein's anomaly, 300–400 times that of the general population.⁵ More recent epidemiological data indicate that this risk, while still present, is far lower. The latest review found no prospective studies that demonstrated an increased risk, despite two cases of Ebstein's anomaly in the lithium treated group, all case control studies were negative, as none of the 222 infants with the anomaly had mothers who took lithium during pregnancy.⁶ The absolute risk of Ebstein's anomaly in babies exposed to lithium is now thought to be 0.05% (1 in 2000).⁷ Because this is still greater than the baseline risk of 1 in 20,000, it is usually recommended by most references that a level II ultrasound and fetal echocardiography be performed at 16 to 18 weeks gestation.⁷⁸

Lithium use in pregnancy has been associated with a number of negative effects in the newborn including depressed neurological status, hypotonia, respiratory distress syndrome, cyanosis, lethargy, and weak suck reflexes. Fortunately most of these adverse effects resolved and most babies made a full recovery within hours to a few weeks.⁶⁷⁹ A 2005 study of lithium levels at time of delivery showed that higher lithium levels were associated with increased complications.⁴ It is therefore recommended to “suspend lithium administration 24–48 hours before a scheduled Cesarean section or induction, or suspend lithium administration at the onset of labor in the event of spontaneous delivery.”⁴ The post-partum rate of mania recurrence can be decreased from 50% to 10 when lithium is started immediately post-partum.¹⁰ Again, the dose should be reduced to pre-partum levels as glomerular filtration rate returns to baseline.⁴

Because of the very high risk of symptom recurrence postpartum, it is important for a woman to stay on her lithium. But can she safely breastfeed? Again, conventional wisdom was that this was potentially dangerous due to possible high levels of lithium in breast milk. The most recent publication of the American Academy of Pediatrics classifies lithium as a drug that should be given to nursing mothers “with caution,” although there is little evidence beyond a handful of case reports as to why.¹¹ More recent publications have shown lithium in breastfeeding to be less problematic than originally thought. Moretti, et al¹² looked at 11 mother-infant pairs and found lithium levels in the breast milk to be 0–30% that of the mother's serum levels, with no adverse effects reported. Viguera et al¹³ studied 10 mother-infant pairs and looked at both breast milk and infant serum levels. They found a “rule of halves”, with lithium concentrations in infant serum (0.16 mEq/liter), breast milk (0.35 mEq/liter), and maternal serum (0.76 mEq/liter)”.¹³ They also found that the lithium was well tolerated by infants, with only minor and transient lab abnormalities after prolonged exposure. Viguera, et al still caution that more research is needed, and that the ideal candidate for continuing lithium while breastfeeding is a patient with “stable maternal mood, lithium monotherapy or at least a simple medication regimen, adherence to infant monitoring recommendations, as well as a healthy infant and a collaborative pediatrician.”¹³

Women with bipolar disorder are still sometimes told to not have children. Often this is due to the concerns about mood stabilizers in pregnancy, including lithium. A recent article in JAMA eloquently illustrates the dilemmas faced by practitioners and patients.¹⁴ Pharmacists are often looked at as sources of information by these women, but one study reported when asked about drugs in pregnancy, 90% of pharmacists directly referred patients to their physician, without giving any information and only 14% referred to the literature to give evidence-based information.¹⁵ By looking more closely at published studies, psychiatric pharmacists can give women some reassurance about taking lithium during pregnancy and lactation.