Lithium and Lactation

Medication use by the nursing mothers is a controversial topic, with the potential for infants to be exposed via breastmilk. This ethical dilemma has led to health professionals, authorities, and parents considering infant formula to be a reasonable alternative to mitigate risk. As a consequence, there is a lack of evidence about the safety and efficacy of many medications during lactation, including lithium¹. Decisions to use lithium during the perinatal period are challenging because information about the efficacy and safety for the mother-child dyad come from observational studies of lactation outcomes, which have important limitations and biases^2,3.

Breastfeeding is an important public health issue because it promotes health, prevents disease, and contributes to reducing health inequalities in mothers and nursing infants. Breastfeeding is also a great benefit to the environment and society⁴. Human milk is uniquely tailored to meet the nutritional needs of human infants, including premature and ill newborns. It has the appropriate balance of nutrients provided in easily digestible and bioavailable forms. Optimal infant and young child feeding practices include exclusive breastfeeding for the first 6 months of life, if possible, followed by combining breastmilk with adequate, safe, and appropriate complementary foods until the infant is at least 1–2 years old⁵.

According to the US National Centers for Disease Control and Prevention, there are few contraindications to breastfeeding. These include maternal infection with HIV, human T-cell lymphotropic virus type 1 or 2, active untreated tuberculosis, or herpes simplex lesions on the breast. Additionally, maternal use of illicit street drugs (i.e., phencyclidine or cocaine), chemotherapeutic agents (drugs interfering with cell replication), and radioactive isotope therapies should contraindicate breastfeeding. Concerning the infants themselves, those with galactosemia should not be breastfed⁶. However, a 2012 clinical report by the American Academy of Pediatrics⁷ indicated that most medications and immunizations are safe to use during lactation.

A common reason for never starting or for interrupting breastfeeding is medication use by the nursing mother. Any pharmacologic therapeutic decision during lactation should be guided by the best available evidence and the importance of benefit for each patient. Factors influencing the decision to breastfeed converge around the advantages and risks of breastfeeding for the mother and infant, the socio-demographic and clinical features of the mother, personal experience and family tradition, the presence of a support system (whether professional or partner, family, social), and personal choice. The optimal time to explore women's preferences for breastfeeding and to educate the family about treatment options during breastfeeding is before they conceive or early in pregnancy⁸. Options include exclusive breastfeeding, breastfeeding supplemented with formula, or exclusive formula feeding.

Bipolar disorder is a chronic mental illness that affects about 350 million people worldwide, equating to 3% of the world population. It affects men and women in comparable rates, often starting before age 25 years, without cultural or ethnic variation^9,10. There seems to be a higher risk for women to suffer bipolar II (hypomania), rapid cycling, and mixed episodes compared with men. Lithium use for the treatment of bipolar disorder has been reported since late 1940s¹¹ and was approved in 1970 by the US Food and Drug Administration (FDA) for the treatment of acute mania and in 1974 for the long-term maintenance of bipolar disorder. It is also prescribed as adjunctive treatment in major depressive disorder and for preventing suicidal behavior in patients with affective disorders^12-13.

Women with bipolar disorder are at high risk of symptom relapse during the perinatal period¹⁴. Although its use during the first trimester has been associated to a dose-dependent increase risk of congenital malformations¹⁵, it has proven to be an effective preventive treatment during perinatal period¹⁶. In relation to treatment at others stages of life, some peculiarities must be considered for the management of lithium treatment during the perinatal period. For example, physiological renal changes during pregnancy¹⁷ may alter the pharmacokinetics of lithium, and its serum concentrations will decline throughout pregnancy. This necessitates preferably weekly monitoring in the third trimester with does adjustment to maintain therapeutic levels¹⁸. Lithium also has a complete placental passage and equilibrates between the maternal and fetal circulation across a wide range of maternal concentrations (0.2–2.6 mEq/L)¹⁹. It has been shown that neonatal serum lithium concentrations >0.64 mEq/L may be associated with an increased rate of neonatal complications such a lethargy, cyanosis, hypothermia, hypotonia, hypothyroidism, hypoglycemia, polyuria, respiratory problems, and poor drinking ability^19-20. Postpartum, serum lithium concentrations in the mother gradually return to their preconception levels, and this presents a risk for lithium intoxication if women have had their dose increased during pregnancy. Lithium serum concentration should be measured twice weekly for the first 2 weeks after delivery and monthly thereafter for the next 3–6 months¹⁸.

Lithium is a cation that transfers easily into breast milk. The recommendations for its use during breastfeeding vary due to the high variability of its diffusion into breastmilk, the secondary risk of lithium toxicity in the newborn, and the risk of relapse associated with sleep deprivation during the period of exclusive maternal breastfeeding²¹. There are limited data about the long-term effects of lithium exposure via breastmilk, but it does seem that the risk of serious adverse events in the nursing infants is relatively low⁷. Two recent systematic reviews concerning clinical lactation and lithium showed that exposure of the nursing infant to lithium is less during breastfeeding than during pregnancy. However, there was also a high degree of heterogeneity between the studies, including exposure durations, the presence of polypharmacy, lithium sampling times, type of breastfeeding, and age of infants^2,3. Nevertheless, it is certainly plausible that nursing infants would be vulnerable to the same side effects as adults, including changes in thyroid and renal functions. In turn, this necessitates regular clinical and blood monitoring (e.g., serum lithium, thyroid stimulating hormone, blood urea nitrogen, and creatinine) immediately postpartum and at regular intervals while breasfeeding²².

Given the many benefits of breastfeeding, some women who may also benefit from lithium in the postpartum period are likely to consider breastfeeding. The professionals involved in this consultation must be adequately trained about the pharmacology of lactation⁸. Women should then have an individualized breastfeeding plan drafted in collaboration with perinatal psychiatrists, obstetricians, pediatricians, midwives, nurses, and family physicians. Research in international collaborative networks would be interesting to increase current evidence to support women in achieving their breastfeeding goals.

References

• ¹
  Amir LH, Grzeskowiak LE, and Kam RL. Ethical issues in use of medications during lactation. J Hum Lact 2020; 36:34-9.
• ²
  Newmark RL, Bogen DL, Wisner KL, Isaac M, Ciolino JD, Clark CT. Risk-benefit assessment on infant exposure to lithium through breast milk: a systematic review of the literature. Int Rev Psychiatry 2019; 31:295-304.
• ³
  Imaz ML, Torra M, Soy D, García-Esteve L, Martin-Santos R. Clinical lactation studies of lithium: a systematic review. Front Pharmacol. 2019 10;10:e1005.
• ⁴
  U.S. Department of Health and Human Services, 2011. The surgeon general's call to action to support breastfeeding. Department of Health and Human Services, Office of the Surgeon General. Washington, DC: U.S.
• ⁵
  World Health Organización/UNICEF. Global strategy for infant and young child feeding. 2003. https://www.who.int/nutrition/publications/infantfeeding/924156228/en/ Accessed August, 2020
  » https://www.who.int/nutrition/publications/infantfeeding/924156228/en/
• ⁶
  Centers for Disease Control and Prevention (CDC). Breastfeeding and special circumstances.https://www.cdc.gov/breastfeeding/breastfeeding-special-circumstances/index.html Accessed August, 2020.
  » https://www.cdc.gov/breastfeeding/breastfeeding-special-circumstances/index.html
• ⁷
  The American Academy of Pediatrics (AAP). Breastfeeding and the use of human milk. Pediatrics 2012;129: 827-41.
• ⁸
  American College of Obstetricians and Gynecologists (ACOG). Optimizing support for breastfeeding as part of obstetric practice. ACOG Committee Opinion No. 756. Obstet Gynecol 2018;132:e187–96.
• ⁹
  Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, Viana MC, Andrade LH, Hu C, Karam EG, Ladea M, Medina-Mora ME, Ono Y, Posada-Villa J, Sagar R, Wells JE, Zarkov Z. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011; 68:241-51.
• ¹⁰
  GBD 2017. Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet 2018; 392:1789-858.
• ¹¹
  Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949: 2 (10):349-352.
• ¹²
  Tondo L, Alda M, Bauer M, Bergink V, Grof P, Hajek T, Lewitka U, Licht RW, Manchia M, Müller-Oerlinghausen B, Nielsen RE, Selo M, Simhandl C, Baldessarini RJ; International Group for Studies of Lithium (IGSLi). Clinical use of lithium salts: guide for users and prescribers. Int J Bipolar Disord. 2019;7:16.
• ¹³
  Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013; 346: f3646.
• ¹⁴
  Viguera AC, Tondo L, Koukopoulos AE, Reginaldi D, Lepri B, Baldessarini RJ. Episodes of mood disorders in 2,252 pregnancies and postpartum periods. Am J Psychiatry. 2011;168:1179-85.
• ¹⁵
  Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017;376:2245-54.
• ¹⁶
  Bergink V, Burgerhout KM, Koorengevel KM, Kamperman AM, Hoogendijk WJ, Lambregtse-van den Berg MP, Kushner SA. Treatment of psychosis and mania in the postpartum period. Am J Psychiatry. 2015;172:115-23.
• ¹⁷
  Feghali M, Venkataramanan R, Steve C. Pharmacokinetics of drugs in pregnancy. Semin. Perinatol. 2015;39: 512-9.
• ¹⁸
  Wesseloo R, Wierdsma AI, van Kamp IL, Munk-Olsen T, Hoogendijk WJG, Kushner SA, Bergink V. Lithium dosing strategies during pregnancy and the postpartum period. Br J Psychiatry. 2017;211:31-6.
• ¹⁹
  Newport DJ, Viguera AC, Beach AJ, Ritchie JC, Cohen LS, Stowe ZN. Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy. Am J Psychiatry. 2005; 162: 2162-70.
• ²⁰
  Kozma C. Neonatal toxicity and transient neurodevelopmental deficits following prenatal exposure to lithium: Another clinical report and a review of the literatura. Am J Med Genet A 2005;132A:441-4.
• ²¹
  Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: Recommendations from clinical practice guidelines. J Affect Disord. 2017;217:266-80.
• ²²
  Viguera AC, Newport DJ, Ritchie J, Stowe Z, Whitfield T, Mogielnicki J, Baldessarini RJ, Zurick A, Cohen LS: Lithium in breast milk and nursing infants: clinical implications. Am J Psychiatry 2007; 164:342-5.

Publication Dates

• Publication in this collection
  12 Mar 2021
• Date of issue
  Sep-Oct 2020

History

• Received
  21 Sept 2020
• Accepted
  21 Sept 2020